Inhibitors of monoacylglycerol lipase and methods of their use

ABSTRACT

Provided herein are compounds which mediate the activity of monoacyglycerol lipase (MAGL). Also provided are pharmaceutical compositions comprising a compound provided herein, and methods for treating, preventing and/or managing a MAGL mediated condition using a compound or pharmaceutical composition as provided herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase entry pursuant to 35 U.S.C. §371 ofInternational Application No. PCT/US2012/057533, filed Sep. 27, 2012,which claims priority to U.S. Provisional Application No. 61/540,928,filed Sep. 29, 2011, and U.S. Provisional Application No. 61/569,096,filed Dec. 9, 2011, the entireties of which are incorporated herein byreference.

BACKGROUND

2-Arachidonoyl glycerol (2-AG) is known to be one of the most importantendocannabinoids, and is a lipid transmitter that serves as endogenousligand for cannabinoid G-protein coupled receptors CB1 and CB2. (Long etal., Proc. Natl. Acad. Sci., 106:20270-20275 (2009)). 2-AG is primarilydegraded by the enzyme monoacylglycerol lipase (MAGL). 2-AG and MAGL arecomponents of the endogenous cannabinoid system, which regulates adiverse number of physiological processes including, but not limited to,pain, cognition, emotionality, neurogeneration, feeding andinflammation. (Di Marzo et al., Chem Biol, 14:741-756 (2007). It wasfurther reported that endogenous cannabinoid system can play a role inregulating a variety of conditions that include, but are not limited to,inflammation, metabolic disorders (e.g., obesity-related conditions andwasting conditions such as cachexias and anorexia), disorders of thecentral nervous system (e.g., disorders associated with neurotoxicityand/or neurotrauma, stroke, multiple sclerosis, spinal cord injury,movement disorders such as basal ganglia disorders, amylotrophic lateralsclerosis, Alzheimer's disease, epilepsy, mental disorders such asanxiety, depression, learning disorders and schizophrenia, sleepdisorders such as insomnia, nausea and/or emesis, and drug addiction),cardiac disorders (e.g., hypertention, circulatory shock, myocardialreperfusion injury and atherosclerosis) and glaucoma (See, e.g., Pacheret al., Pharmacological Reviews, 58:389-462(2006); and Pillarisetti etal., Drug Discovery Today, 597:1-14(2009)). Thus, a need exists for aneffective inhibitor for MAGL as a therapy for a wide variety ofendogenous cannabinoid system related conditions or disorders.

It has been reported that MAGL is highly expressed in aggressive humancancer cells and primary tumors, where it regulates a fatty acid networkenriched in oncogenic signaling lipids that promotes migration,invasion, survival, and in vivo tumor growth (Nomura et al., Cell,140:49-61 (2010)). Overexpression of MAGL is found to increase the freefatty acid (FFA) levels and the aggressiveness of cancercells—phenotypes that are reversed by an MAGL inhibitor. Id. Thus, aneed also exists for an effective inhibitor for MAGL as a therapy forcancer.

SUMMARY

Provided herein are compounds, and pharmaceutical compositions thereof,which are effective inhibitors of monoacyglycerol lipase (MAGL).

Also provided herein are methods for treating, preventing and/ormanaging an MAGL related condition or disorder by administering atherapeutically or prophylactically effective amount of a compoundprovided herein, or a pharmaceutical composition thereof, to a patient.

DETAILED DESCRIPTION 1. Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. As provided herein, and unless otherwisespecified, the chemical elements are identified in accordance with thePeriodic Table of the Elements, CAS version, Handbook of Chemistry andPhysics, 75^(th) Ed., inside cover, and specific functional groups aregenerally defined as described therein. Additionally, general principlesof organic chemistry, as well as specific functional moieties andreactivity, are described in Organic Chemistry, Thomas Sorrell,University Science Books, Sausalito, 1999; Smith and March March'sAdvanced Organic Chemistry, 5^(th) Edition, John Wiley & Sons, Inc., NewYork, 2001; Larock, Comprehensive Organic Transformations, VCHPublishers, Inc., New York, 1989; Carruthers, Some Modern Methods ofOrganic Synthesis, 3^(rd) Edition, Cambridge University Press,Cambridge, 1987; the entire contents of each of which are incorporatedherein by reference.

While specific embodiments have been discussed, the specification isillustrative only and not restrictive. Many variations of thisdisclosure will become apparent to those skilled in the art upon reviewof this specification.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this specification pertains.

As used in the specification and claims, the singular form “a”, “an” and“the” includes plural references unless the context clearly dictatesotherwise.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included. The term “about” when referring toa number or a numerical range means that the number or numerical rangereferred to is an approximation within experimental variability (orwithin statistical experimental error), and thus the number or numericalrange can vary from, for example, between 1% and 15%, between 1% and10%, between 1% and 5%, between 0.5% and 5%, and between 0.5% and 1%, ofthe stated number or numerical range. As disclosed herein, everyinstance where a number or numerical range preceded by the term “about”also includes the embodiment of the given number(s). For example, “about3° C.” discloses the embodiment of the temperature being “3° C.”. Theterms “about” and “approximately” are used completely interchangeablethroughout the disclosure. The term “between” includes the endpointnumbers on both limits of the range. For example, the range described by“between 3 and 5” is inclusive of the numbers “3” and “5”.

Certain compounds provided herein can comprise one or more asymmetriccenters, and thus can exist in various isomeric forms, e.g.,stereoisomers and/or diastereomers. Thus, compounds and pharmaceuticalcompositions thereof can be in the form of an individual enantiomer,diastereomer or geometric isomer, or can be in the form of a mixture ofstereoisomers. In certain embodiments, the compounds provided herein areenantiopure compounds. In certain other embodiments, mixtures ofstereoisomers or diastereomers are provided.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A mixture of a pair of enantiomers in anyproportion can be known as a “racemic” mixture. The term “(±)” is usedto designate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is anenantiomer, the stereochemistry at each chiral carbon can be specifiedby either R or S. Resolved compounds whose absolute configuration isunknown can be designated (+) or (−) depending on the direction (dextro-or levorotatory) which they rotate plane polarized light at thewavelength of the sodium D line. Certain of the compounds describedherein contain one or more asymmetric centers and can thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that can bedefined, in terms of absolute stereochemistry at each asymmetric atom,as (R)- or (S)-. The present chemical entities, pharmaceuticalcompositions and methods are meant to include all such possible isomers,including racemic mixtures, optically substantially pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers can beprepared, for example, using chiral synthons or chiral reagents, orresolved using conventional techniques.

The “enantiomeric excess” or “% enantiomeric excess” of a compositioncan be calculated using the equation shown below. In the example shownbelow, a composition contains 90% of one enantiomer, e.g., the Senantiomer, and 10% of the other enantiomer, e.g., the R enantiomer.

ee=(90−10)/100=80%.

Thus, a composition containing 90% of one enantiomer and 10% of theother enantiomer is said to have an enantiomeric excess of 80%. Somecompositions described herein contain an enantiomeric excess of at leastabout 50%, about 75%, about 90%, about 95%, or about 99% of the Senantiomer. In other words, the compositions contain an enantiomericexcess of the S enantiomer over the R enantiomer. In other embodiments,some compositions described herein contain an enantiomeric excess of atleast about 50%, about 75%, about 90%, about 95%, or about 99% of the Renantiomer. In other words, the compositions contain an enantiomericexcess of the R enantiomer over the S enantiomer.

For instance, an isomer/enantiomer can, in some embodiments, be providedsubstantially free of the corresponding enantiomer, and can also bereferred to as “optically enriched,” “enantiomerically enriched,”“enantiomerically pure” and “non-racemic,” as used interchangeablyherein. These terms refer to compositions in which the percent by weightof one enantiomer is greater than the amount of that one enantiomer in acontrol mixture of the racemic composition (e.g., greater than about 1:1by weight). For example, an enantiomerically enriched preparation of theS enantiomer, means a preparation of the compound having greater thanabout 50% by weight of the S enantiomer relative to the R enantiomer,such as at least about 75% by weight, further such as at least about 80%by weight. In some embodiments, the enrichment can be much greater thanabout 80% by weight, providing a “substantially enantiomericallyenriched,” “substantially enantiomerically pure” or a “substantiallynon-racemic” preparation, which refers to preparations of compositionswhich have at least about 85% by weight of one enantiomer relative toother enantiomer, such as at least about 90% by weight, and further suchas at least 95% by weight. In certain embodiments, the compound providedherein is made up of at least about 90% by weight of one enantiomer. Inother embodiments, the compound is made up of at least about 95%, about98%, or about 99% by weight of one enantiomer.

In some embodiments, the compound is a racemic mixture of (S)- and(R)-isomers. In other embodiments, provided herein is a mixture ofcompounds wherein individual compounds of the mixture existpredominately in an (S)- or (R)-isomeric configuration. For example, thecompound mixture has an (S)-enantiomeric excess of greater than about55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about99.5%, or more. In other embodiments, the compound mixture has an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about about 60% to about 99.5%, greater than about 65% toabout 99.5%, greater than about 70% to about 99.5%, greater than about75% to about 99.5%, greater than about 80% to about 99.5%, greater thanabout 85% to about 99.5%, greater than about 90% to about 99.5%, greaterthan about 95% to about 99.5%, greater than about 96% to about 99.5%,greater than about 97% to about 99.5%, greater than about 98% to greaterthan about 99.5%, greater than about 99% to about 99.5%, or more.

In other embodiments, the compound mixture has an (R)-enantiomericpurity of greater than about 55%, about 60%, about 65%, about 70%, about75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%,about 98%, about 99%, about 99.5% or more. In some other embodiments,the compound mixture has an (R)-enantiomeric excess of greater thanabout 55% to about 99.5%, greater than about about 60% to about 99.5%,greater than about 65% to about 99.5%, greater than about 70% to about99.5%, greater than about 75% to about 99.5%, greater than about 80% toabout 99.5%, greater than about 85% to about 99.5%, greater than about90% to about 99.5%, greater than about 95% to about 99.5%, greater thanabout 96% to about 99.5%, greater than about 97% to about 99.5%, greaterthan about 98% to greater than about 99.5%, greater than about 99% toabout 99.5% or more.

In other embodiments, the compound mixture contains identical chemicalentities except for their stereochemical orientations, namely (S)- or(R)-isomers. For example, if a compound disclosed herein has —CH(R)—unit, and R is not hydrogen, then the —CH(R)— is in an (S)- or(R)-stereochemical orientation for each of the identical chemicalentities. In some embodiments, the mixture of identical chemicalentities is a racemic mixture of (S)- and (R)-isomers. In anotherembodiment, the mixture of the identical chemical entities (except fortheir stereochemical orientations), contain predominately (S)-isomers orpredominately (R)-isomers. For example, the (S)-isomers in the mixtureof identical chemical entities are present at about 55%, about 60%,about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more,relative to the (R)-isomers. In some embodiments, the (S)-isomers in themixture of identical chemical entities are present at an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about about 60% to about 99.5%, greater than about 65% toabout 99.5%, greater than about 70% to about 99.5%, greater than about75% to about 99.5%, greater than about 80% to about 99.5%, greater thanabout 85% to about 99.5%, greater than about 90% to about 99.5%, greaterthan about 95% to about 99.5%, greater than about 96% to about 99.5%,greater than about 97% to about 99.5%, greater than about 98% to greaterthan about 99.5%, greater than about 99% to about 99.5% or more.

In another embodiment, the (R)-isomers in the mixture of identicalchemical entities (except for their stereochemical orientations), arepresent at about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%,about 99%, about 99.5%, or more, relative to the (S)-isomers. In someembodiments, the (R)-isomers in the mixture of identical chemicalentities (except for their stereochemical orientations), are present ata (R)-enantiomeric excess greater than about 55% to about 99.5%, greaterthan about about 60% to about 99.5%, greater than about 65% to about99.5%, greater than about 70% to about 99.5%, greater than about 75% toabout 99.5%, greater than about 80% to about 99.5%, greater than about85% to about 99.5%, greater than about 90% to about 99.5%, greater thanabout 95% to about 99.5%, greater than about 96% to about 99.5%, greaterthan about 97% to about 99.5%, greater than about 98% to greater thanabout 99.5%, greater than about 99% to about 99.5%, or more.

Furthermore, certain compounds, as described herein, can have one ormore double bonds that can exist as either the Z or E isomer, unlessotherwise indicated. The compounds as individual isomers substantiallyfree of other isomers and alternatively, as mixtures of various isomers,e.g., racemic mixtures of stereoisomers, are therefore also encompassedherein. In addition to the above-mentioned compounds per se, alsoprovided are pharmaceutically acceptable derivatives of these compoundsand compositions comprising one or more compounds.

Where a particular enantiomer is indicated, it can, in some embodiments,be provided substantially free of the corresponding enantiomer, and canalso be referred to as “optically pure” or “optically enriched.” Theseterms, as used herein, means that the compound is made up of asignificantly greater proportion of one enantiomer. In certainembodiments, the compound is made up of at least about 90% by weight ofa given enantiomer. In other embodiments the compound is made up of atleast about 95%, 98%, or 99% by weight of a given enantiomer. Someenantiomers can be isolated from racemic mixtures by any method known tothose skilled in the art, including, but not limited to, chiral highpressure liquid chromatography (HPLC) and the formation andcrystallization of chiral salts or prepared by asymmetric syntheses.See, for example, Jacques, et al., Enantiomers, Racemates andResolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al.,Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of CarbonCompounds (McGraw-Hill, N.Y., 1962); Wilen, S. H. Tables of ResolvingAgents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of NotreDame Press, Notre Dame, Ind. 1972).

As used herein, a “direct bond” or “covalent bond” refers to a singlebond.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

As used herein, the term “boronic acid” refers to any chemical compoundcomprising a —B(OH)₂ moiety. Arylboronic acid compounds readily formoligomeric anhydrides by dehydration of the boronic acid moiety (see,for example, Snyder et al., J. Am. Chem. Soc. (1958) 80: 3611). Thus,unless otherwise apparent from context, the term “boronic acid” isexpressly intended to encompass free boronic acids, oligomericanhydrides, including, but not limited to, dimers, trimers, andtetramers, and mixtures thereof. Furthermore, the term “boronic ester”refers to any chemical compound comprising a —B(OR)₂ moiety. The term“borinic acid” refers to any chemical compound comprising a —B(R)OHmoiety. The term “borinic ester” refers to any chemical compoundcomprising a —B(R)OR moiety. In some embodiments, R can be R^(∘) asdefined below.

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo,—Br), and iodine (iodo, —I).

The term “aliphatic” or “aliphatic group”, as used herein, denotes ahydrocarbon moiety that can be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spiro-fusedpolycyclic) and can be completely saturated or can contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-6 carbon atoms. In someembodiments, aliphatic groups contain 1-4 carbon atoms, and in yet otherembodiments aliphatic groups contain 1-3 carbon atoms. Suitablealiphatic groups include, but are not limited to, linear or branched,alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “unsaturated”, as used herein, means that a moiety has one ormore double or triple bonds.

The terms “cycloaliphatic”, “carbocycle”, or “carbocyclic”, used aloneor as part of a larger moiety, refer to a saturated or partiallyunsaturated cyclic aliphatic monocyclic or bicyclic ring systems, asdescribed herein, having from 3 to 10 members, wherein the aliphaticring system is optionally substituted as defined above and describedherein. Partially unsaturated cycloalkyl groups can be termed“cycloalkenyl” if the carbocycle contains at least one double bond, or“cycloalkynyl” if the carbocycle contains at least one triple bond.Whenever it appears herein, a numerical range such as “3 to 10” refersto each integer in the given range; e.g., “3 to 10 carbon atoms” meansthat the cycloalkyl group can consist of 3 carbon atoms, 4 carbon atoms,5 carbon atoms, etc., up to and including 10 carbon atoms. The term“cycloalkyl” also includes bridged and spiro-fused cyclic structurescontaining no heteroatoms. The term also includes monocyclic orfused-ring polycyclic (i.e., rings which share adjacent pairs of ringatoms) groups. Illustrative examples of cycloalkyl groups include, butare not limited to the following moieties: C₃₋₆ carbocyclyl groupsinclude, without limitation, cyclopropyl (C₃), cyclobutyl (C₄),cyclopentyl (C₅), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl(C₆), cyclohexadienyl (C₆) and the like. Examples of C₃₋₈ carbocyclylgroups include, but are not limited to, the aforementioned C₃₋₆carbocyclyl groups as well as cycloheptyl (C₇), cycloheptadienyl (C₇),cycloheptatrienyl (C₇), cyclooctyl (C₈), bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl, and the like. Examples of C₃₋₁₀ carbocyclylgroups include, but are not limited to, the aforementioned C₃₋₈carbocyclyl groups as well as octahydro-1H-indenyl,decahydronaphthalenyl, spiro[4.5]decanyl and the like. In someembodiments, the cycloalkyl is a C₃-C₈ cycloalkyl radical. In someembodiments, the cycloalkyl has 3-6 carbons. The terms “cycloaliphatic”,“carbocycle” or “carbocyclic” also include, but are not limited to,aliphatic rings that are fused to one or more aromatic or nonaromaticrings, such as decahydronaphthyl or tetrahydronaphthyl, where theradical or point of attachment is on the aliphatic ring.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten carbon atoms (e.g., C₁-C₁₀ alkyl).Whenever it appears herein, a numerical range such as “1 to 10” refersto each integer in the given range; e.g., “1 to 10 carbon atoms” meansthat the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated. In some embodiments, the term “alkyl,”as used herein, refers to saturated, straight- or branched-chainhydrocarbon radicals derived from an aliphatic moiety containing betweenone and six carbon atoms by removal of a single hydrogen atom. In someembodiments, the term “alkyl” also contain cycloalkyl groups. In someembodiments, the alkyl group employed herein contains 1-5 carbon atoms.In another embodiment, the alkyl group employed contains 1-4 carbonatoms. In still other embodiments, the alkyl group contains 1-3 carbonatoms. In yet another embodiments, the alkyl group contains 1-2 carbons.Examples of alkyl radicals include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl,iso-pentyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl,n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, and the like.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to ten carbon atoms (i.e.,C₂-C₁₀ alkenyl). Whenever it appears herein, a numerical range such as“2 to 10” refers to each integer in the given range; e.g., “2 to 10carbon atoms” means that the alkenyl group can consist of 2 carbonatoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. Incertain embodiments, an alkenyl comprises two to eight carbon atoms. Inother embodiments, an alkenyl comprises two to five carbon atoms (e.g.,C₂-C₅ alkenyl). The alkenyl is attached to the parent molecularstructure by a single bond, for example, ethenyl (i.e., vinyl),prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl,and the like. The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include, but are not limited to, ethenyl (C₂),1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄),butadienyl (C₄) and the like. Examples of C₂₋₆ alkenyl groups include,but are not limited to, the aforementioned C₂₋₄ alkenyl groups as wellas pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆) and the like.Additional examples of alkenyl include, but are not limited to, heptenyl(C₇), octenyl (C₈), octatrienyl (C₈) and the like.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to ten carbon atoms (i.e., C₂-C₁₀alkynyl). Whenever it appears herein, a numerical range such as “2 to10” refers to each integer in the given range; e.g., “2 to 10 carbonatoms” means that the alkynyl group can consist of 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms. In certainembodiments, an alkynyl comprises two to eight carbon atoms. In otherembodiments, an alkynyl has two to five carbon atoms (e.g., C₂-C₅alkynyl). The alkynyl is attached to the parent molecular structure by asingle bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl,and the like.

The term “alkoxy” refers to the group —O-alkyl, including from 1 to 10carbon atoms of a straight, branched, cyclic configuration andcombinations thereof, attached to the parent molecular structure throughan oxygen. Examples include, but are not limited to, methoxy, ethoxy,propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. “Loweralkoxy” refers to alkoxy groups containing one to six carbons. In someembodiments, C₁-C₄ alkoxy is an alkoxy group which encompasses bothstraight and branched chain alkyls of from 1 to 4 carbon atoms.

The term “alkoxycarbonyl” refers to a group of the formula(alkoxy)(C═O)— attached to the parent molecular structure through thecarbonyl carbon having from 1 to 10 carbon atoms. Thus a C₁-C₆alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atomsattached through its oxygen to a carbonyl linker. The C₁-C₆ designationdoes not include the carbonyl carbon in the atom count. “Loweralkoxycarbonyl” refers to an alkoxycarbonyl group wherein the alkylportion of the alkoxy group is a lower alkyl group. In some embodiments,C₁-C₄ alkoxy is an alkoxy group which encompasses both straight andbranched chain alkoxy groups of from 1 to 4 carbon atoms.

“Acyl” refers to R—C(O)— groups such as, but not limited to,(alkyl)-C(O)—, (alkenyl)-C(O)—, (alkenyl)-C(O)—, (aryl)-C(O)—,(cycloalkyl)-C(O)—, (heteroaryl)-C(O)—, (heteroalkyl)-C(O)—, and(heterocycloalkyl)-C(O)—, wherein the group is attached to the parentmolecular structure through the carbonyl functionality. In someembodiments, it is a C₁-C₁₀ acyl radical which refers to the totalnumber of chain or ring atoms of the, for example, alkyl, alkenyl,alkynyl, aryl, cyclohexyl, heteroaryl or heterocycloalkyl portion plusthe carbonyl carbon of acyl. For example, a C₄-acyl has three other ringor chain atoms plus carbonyl. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms.

“Acyloxy” refers to a R(C═O)O— radical wherein “R” can be alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl,cyclohexyl, heteroaryl or heterocycloalkyl, which are as describedherein. The acyloxy group is attached to the parent molecular structurethrough the oxygen functionality. In some embodiments, an acyloxy groupis a C₁-C₄ acyloxy radical which refers to the total number of chain orring atoms of the alkyl, alkenyl, alkynyl, aryl, cyclohexyl, heteroarylor heterocycloalkyl portion of the acyloxy group plus the carbonylcarbon of acyl, i.e., a C₄-acyloxy has three other ring or chain atomsplus carbonyl. If the R radical is heteroaryl or heterocycloalkyl, thehetero ring or chain atoms contribute to the total number of chain orring atoms.

“Amino” or “amine” refers to a —N(R^(b))₂, —N(R^(b))R^(b)—, or—R^(b)N(R^(b))R^(b)— radical group, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.When a —N(R^(b))₂ group has two R^(b) other than hydrogen, they can becombined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-memberedring. For example, —N(R^(b))₂ is meant to include, but not be limitedto, 1-pyrrolidinyl and 4-morpholinyl.

The terms “amine” and “amino” also refer to N-oxides of the groups—N⁺(H)(R^(a))O⁻, and —N⁺(R^(a))(R^(a))O—, R^(a) as described above,where the N-oxide is bonded to the parent molecular structure throughthe N atom. N-oxides can be prepared by treatment of the correspondingamino group with, for example, hydrogen peroxide orm-chloroperoxybenzoic acid. The person skilled in the art is familiarwith reaction conditions for carrying out the N-oxidation.

“Amide” or “amido” refers to a chemical moiety with formula—C(O)N(R^(b))₂ or —NR^(b)C(O)R^(b), where R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.In some embodiments, this radical is a C₁-C₄ amido or amide radical,which includes the amide carbonyl in the total number of carbons in theradical. When a —C(O)N(R^(b))₂ has two R^(b) other than hydrogen, theycan be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or7-membered ring. For example, N(R^(b))₂ portion of a —C(O)N(R^(b))₂radical is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic andbicyclic ring systems having a total of five to 10 ring members, whereinat least one ring in the system is aromatic and wherein each ring in thesystem contains three to seven ring members. The term “aryl” can be usedinterchangeably with the term “aryl ring”. In certain embodiments,“aryl” refers to an aromatic ring system which includes, but not limitedto, phenyl, biphenyl, naphthyl, anthracyl and the like, which can bearone or more substituents. Also included within the scope of the term“aryl”, as it is used herein, is a group in which an aromatic ring isfused to one or more non-aromatic rings, such as indanyl, phthalimidyl,naphthimidyl, phenantriidinyl, or tetrahydronaphthyl, and the like.

“Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” include alkyl,alkenyl and alkynyl radicals, respectively, which have one or moreskeletal chain atoms selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Anumerical range can be given, e.g., C₁-C₄ heteroalkyl which refers tothe chain length in total, which in this example is 4 atoms long. Forexample, a —CH₂OCH₂CH₃ radical is referred to as a “C₄” heteroalkyl,which includes the heteroatom center in the atom chain lengthdescription. Connection to the parent molecular structure can be througheither a heteroatom or a carbon in the heteroalkyl chain. For example,an N-containing heteroalkyl moiety refers to a group in which at leastone of the skeletal atoms is a nitrogen atom. One or more heteroatom(s)in the heteroalkyl radical can be optionally oxidized. One or morenitrogen atoms, if present, can also be optionally quaternized. Forexample, heteroalkyl also includes skeletal chains substituted with oneor more nitrogen oxide (—O—) substituents. Exemplary heteroalkyl groupsinclude, without limitation, ethers such as methoxyethanyl(—CH₂CH₂OCH₃), ethoxymethanyl (—CH₂OCH₂CH₃), (methoxymethoxy)ethanyl(—CH₂CH₂OCH₂OCH₃), (methoxymethoxy)methanyl (—CH₂OCH₂OCH₃) and(methoxyethoxy)methanyl (—CH₂OCH₂CH₂OCH₃) and the like; amines such as—CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)₂, —CH₂NHCH₂CH₃, —CH₂N(CH₂CH₃)(CH₃) and thelike.

The terms “heteroaryl” and “heteroar-”, used alone or as part of alarger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer togroups having 5 to 10 ring atoms, such as 5, 6, or 9 ring atoms; having6, 10, or 14 it electrons shared in a cyclic array; and having, inaddition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes anyoxidized form of nitrogen or sulfur, and any quaternized form of a basicnitrogen. Heteroaryl groups include, without limitation, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and“heteroar-”, as used herein, also include groups in which aheteroaromatic ring is fused to one or more aryl, cycloaliphatic, orheterocyclyl rings, where the radical or point of attachment is on theheteroaromatic ring. Non-limiting examples include indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Aheteroaryl group can be mono- or bicyclic.

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, phosphorous, and sulfur (“5-10 memberedheteroaryl”). In some embodiments, a heteroaryl group is a 5-8 memberedaromatic ring system having ring carbon atoms and 1-4 ring heteroatomsprovided in the aromatic ring system, wherein each heteroatom isindependently selected from nitrogen, oxygen, phosphorous, and sulfur(“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group isa 5-6 membered aromatic ring system having ring carbon atoms and 1-4ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorous,and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen,oxygen, phosphorous, and sulfur. In some embodiments, the 5-6 memberedheteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen,phosphorous, and sulfur. In some embodiments, the 5-6 memberedheteroaryl has 1 ring heteroatom selected from nitrogen, oxygen,phosphorous, and sulfur.

Examples of heteroaryls include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.,thienyl).

The term “heteroaryl” can be used interchangeably with the terms“heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of whichterms include rings that are optionally substituted. The term“heteroaralkyl” refers to an alkyl group substituted by a heteroaryl,wherein the alkyl and heteroaryl portions independently are optionallysubstituted.

As used herein, the terms “heterocycle”, “heterocyclyl”, “heterocyclicradical”, and “heterocyclic ring” are used interchangeably and refer toa stable 5- to 8-membered monocyclic or 7-14-membered bicyclicheterocyclic moiety that is either saturated or partially unsaturated,and having, in addition to carbon atoms, one or more, such as one tofour, heteroatoms, as defined above. The term “heterocyclylalkyl” refersto an alkyl group substituted by a heterocyclyl, wherein the alkyl andheterocyclyl portions independently are optionally substituted. Whenused in reference to a ring atom of a heterocycle, the term “nitrogen”includes a substituted nitrogen. As an example, in a saturated orpartially unsaturated ring having 0-3 heteroatoms selected from oxygen,sulfur or nitrogen, the nitrogen can be N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR (as inN-substituted pyrrolidinyl).

Heterocyclyl polycyclic ring systems can include one or more heteroatomsin one or both rings. In some embodiments, a heterocyclyl group is a3-10 membered non-aromatic ring system having ring carbon atoms and 1-4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“3-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl groupis a 5-6 membered non-aromatic ring system having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In someembodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclylhas 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

A heterocyclic ring can be attached to its pendant group at anyheteroatom or carbon atom that results in a stable structure and any ofthe ring atoms can be optionally substituted. Examples of such saturatedor partially unsaturated heterocyclic radicals include, withoutlimitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl,pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl,dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl,and quinuclidinyl. The terms “heterocycle”, “heterocyclyl”,“heterocyclyl ring”, “heterocyclic group”, “heterocyclic moiety”, and“heterocyclic radical”, are used interchangeably herein, and alsoinclude groups in which a heterocyclyl ring is fused to one or morearyl, heteroaryl, or cycloaliphatic rings, such as indolinyl,3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, wherethe radical or point of attachment is on the heterocyclyl ring.

Exemplary 3-membered heterocyclyls containing 1 heteroatom include,without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-memberedheterocyclyls containing 1 heteroatom include, without limitation,azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclylscontaining 1 heteroatom include, without limitation, tetrahydrofuranyl,dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl,dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-memberedheterocyclyls containing 2 heteroatoms include, without limitation,dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-memberedheterocyclyls containing 3 heteroatoms include, without limitation,triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-memberedheterocyclyl groups containing 1 heteroatom include, without limitation,piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary6-membered heterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, dioxanyl, andtriazinanyl. Exemplary 7-membered heterocyclyl groups containing 1heteroatom include, without limitation, azepanyl, oxepanyl andthiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

“Oxo” refers to the ═O radical.

“Sulfanyl”, “sulfide”, and “thio” each refer to the radical —S—R^(b),wherein R^(b) is selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. For instance, an “alkylthio” refers to the“alkyl-S-” radical, and “arylthio” refers to the “aryl-S-” radical, eachof which are bound to the parent molecular group through the S atom. Theterms “sulfide”, “thiol”, “mercapto”, and “mercaptan” can also eachrefer to the group —R^(b)SH.

“Sulfinyl” or “sulfoxide” refers to the —S(O)—R^(b) radical, wherein for“sulfinyl”, R^(b) is H and for “sulfoxide”, R^(b) is selected fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded through a chaincarbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl(bonded through a ring carbon), heterocycloalkylalkyl, heteroaryl(bonded through a ring carbon) or heteroarylalkyl, unless statedotherwise in the specification, each of which moiety can itself beoptionally substituted as described herein.

“Sulfonyl” or “sulfone” refers to the —S(O₂)—R^(b) radical, whereinR^(b) is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfonamidyl” or “sulfonamido” refers to the following radicals:—S(═O)₂—N(R^(b))₂, —N(R^(b))—S(═O)₂—R^(b), —S(═O)₂—N(R^(b))—, or—N(R^(b))—S(═O)₂—, where each R^(b) is independently selected fromhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein. The R^(b) groups in—S(═O)₂—N(R^(b))₂ can be taken together with the nitrogen to which theyare attached to form a 4-, 5-, 6-, or 7-membered heterocyclyl ring. Insome embodiments, the term designates a C₁-C₄ sulfonamido, wherein eachR^(b) in the sulfonamido contains 1 carbon, 2 carbons, 3 carbons, or 4carbons total.

“Sulfoxyl” or “sulfoxide” refers to a —S(═O)₂OH radical.

“Sulfonate” refers to a —S(═O)₂—OR^(b) radical, wherein R^(b) isselected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

As used herein, the term “partially unsaturated” refers to a ring moietythat includes at least one double or triple bond. The term “partiallyunsaturated” is intended to encompass rings having multiple sites ofunsaturation, but is not intended to include aryl or heteroarylmoieties, as herein defined.

As described herein, compounds provided herein can contain “optionallysubstituted” moieties. In general, the term “substituted”, whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group can have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure can besubstituted with more than one substituent selected from a specifiedgroup, the substituent can be either the same or different at everyposition. Combinations of substituents are those that result in theformation of stable or chemically feasible compounds. The term “stable”,as used herein, refers to compounds that are not substantially alteredwhen subjected to conditions to allow for their production, detection,and, in certain embodiments, their recovery, purification, and use forone or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which can besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which can be substitutedwith R^(∘); —CH═CHPh, which can be substituted with R^(∘); —NO₂; —CN;—N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘); —N(R^(∘))C(S)R^(∘);—(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘) ₂;—(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘),—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘)₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight orbranched)alkylene)O—N(R^(∘) ₂; or —(C₁₋₄ straight orbranched)alkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) can be substitutedas defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur, or, notwithstanding the definition above, twoindependent occurrences of R^(∘), taken together with their interveningatom(s), form a 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, which can be substituted as definedbelow.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(), -(haloR^()),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(), —(CH₂)₀₋₂CH(OR^())₂; —O(haloR^()), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(),—(CH₂)₀₋₂SR^(), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂ NH₂, —(CH₂)₀₋₂NHR^(),—(CH₂)₀₋₂NR^() ₂, —NO₂, —SiR^() ₃, —OSiR^() ₃, —C(O)SR^(), —(C₁₋₄straight or branched alkylene)C(O)OR^(), or −SSR^() wherein each R^()is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include, but are not limited to, thefollowing: ═O, ═S, ═NNR*₂, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*,═NOR*, —O(C(R*₂))₂₋₃O—, or —S(C(R*₂))₂₋₃S—, wherein each independentoccurrence of R* is selected from hydrogen, C₁₋₆ aliphatic which can besubstituted as defined below, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. Suitabledivalent substituents that are bound to vicinal substitutable carbons ofan “optionally substituted” group include: —O(CR*₂)₂₋₃O—, wherein eachindependent occurrence of R* is selected from hydrogen, C₁₋₆ aliphaticwhich can be substituted as defined below, or an unsubstituted5-6-membered saturated, partially unsaturated, or aryl ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(), -(haloR^()), —OH, —OR^(), —O(haloR^()), —CN, —C(O)OH,—C(O)OR^(), —NH₂, —NHR^(), —NR^() ₂, or —NO₂, wherein each R^() isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which can be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(), -(haloR^()), —OH, —OR^(), —O(haloR^()), —CN,—C(O)OH, —C(O)OR^(), —NH₂, —NHR^(), —NR^() ₂, or —NO₂, wherein eachR^() is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

As used herein, a “pharmaceutically acceptable form thereof” includesany pharmaceutically acceptable salts, prodrugs, tautomers, isomers,and/or isotopically labeled derivatives of a compound provided herein,as defined below and herein.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge etal., describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds providedherein include those derived from suitable inorganic and organic acidsand bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid ormalonic acid or by using other methods used in the art such as ionexchange. Other pharmaceutically acceptable salts include, but are notlimited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include, but are not limitedto, alkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄salts. Representative alkali or alkaline earth metal salts include, butare not limited to, sodium, lithium, potassium, calcium, magnesium, andthe like. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, and ethanolamine. In someembodiments, the pharmaceutically acceptable base addition salt ischosen from ammonium, potassium, sodium, calcium, and magnesium salts.

As used herein, the term “prodrug” refers to a derivative of a parentcompound that requires transformation within the body in order torelease the parent compound. A prodrug can be inactive when administeredto a subject, but is converted in vivo to an active compound, forexample, by hydrolysis (e.g., hydrolysis in blood). In certain cases, aprodrug has improved physical and/or delivery properties over the parentcompound. Prodrugs are typically designed to enhance pharmaceuticallyand/or pharmacokinetically based properties associated with the parentcompound. The advantage of a prodrug can lie in its physical properties,such as enhanced water solubility for parenteral administration atphysiological pH compared to the parent compound, or it enhancesabsorption from the digestive tract, or it can enhance drug stabilityfor long-term storage. (see, e.g., Bundgard, H., Design of Prodrugs(1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugsis provided in Higuchi, T., et al., “Pro-drugs as Novel DeliverySystems,” A.C.S. Symposium Series, Vol. 14, and in BioreversibleCarriers in Drug Design, ed. Edward B. Roche, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporated infull by reference herein.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a subject. Prodrugs of an active compound, as describedherein, can be prepared by modifying functional groups present in theactive compound in such a way that the modifications are cleaved, eitherin routine manipulation or in vivo, to the parent active compound.Prodrugs include compounds wherein a hydroxy, amino or mercapto group isbonded to any group that, when the prodrug of the active compound isadministered to a subject, cleaves to form a free hydroxy, free amino orfree mercapto group, respectively. Examples of prodrugs include, but arenot limited to, acetate, formate and benzoate derivatives of an alcoholor acetamide, formamide and benzamide derivatives of an amine functionalgroup in the active compound and the like. Other examples of prodrugsinclude compounds that comprise —NO, —NO₂, —ONO, or —ONO₂ moieties.Prodrugs can typically be prepared using well-known methods, such asthose described in Burger's Medicinal Chemistry and Drug Discovery,172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design ofProdrugs (H. Bundgaard ed., Elselvier, N.Y., 1985).

For example, if a disclosed compound or a pharmaceutically acceptableform of the compound contains a carboxylic acid functional group, aprodrug can comprise a pharmaceutically acceptable ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl havingfrom 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as (3-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Similarly, if a disclosed compound or a pharmaceutically acceptable formof the compound contains an alcohol functional group, a prodrug can beformed by the replacement of the hydrogen atom of the alcohol group witha group such as (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

If a disclosed compound or a pharmaceutically acceptable form of thecompound incorporates an amine functional group, a prodrug can be formedby the replacement of a hydrogen atom in the amine group with a groupsuch as R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are eachindependently (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, a naturalα-aminoacyl or natural α-aminoacyl-natural α-aminoacyl, —C(OH)C(O)OY¹wherein Y¹ is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄)alkyl and Y³ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl ormono-N- or di-N,N—(C₁-C₆)alkylaminoalkyl, C(Y⁴)Y⁵ wherein Y⁴ is H ormethyl and Y⁵ is mono-N- or di-N,N—(C₁-C₆)alkylamino, morpholino,piperidin-1-yl or pyrrolidin-1-yl.

The compounds provided herein readily undergo dehydration to formoligomeric anhydrides by dehydration of the boronic acid moiety to formdimers, trimers, and tetramers, and mixtures thereof. These oligomericspecies hydrolyze under physiological conditions to reform the boronicacid. As such, the oligomeric anhydrides are contemplated as a “prodrug”of the compounds provided herein, and can be used in the treatment ofdisorder and/or conditions a wherein the inhibition of MAGL provides atherapeutic effect.

Prodrugs of boronic acids can be in the form of the “ate” form when theboron is in its tetrahedral form. Examples of this are trifluoroborateswhich will rapidly hydrolyze to the boronic acid. Salt forms (e.g., Na⁺,Li⁺, Mg²⁺, Ca²⁺, and the like) of the boronic acid could be consideredto exist as an “ate” as well. Other 1,2 and 1,3 hydroxy sugars can beused to form “ate” prodrugs as depicted above, such as, for example,glycerol, erythritol, threitol, ribitol, arabinitol, xylitol, allitol,altritol, galactitol, sorbitol, mannitol, and iditol. Other sugars whichuseful in the formation of prodruts include, but are not limited to,maltitol, lactitol, and isomalt; other monosaccharides which includehexoses (e.g., allose, altrose, glucose, mannose, gulose, idose,galactose, talose) and pentoses (e.g., ribose, arabinaose, xylose,lyxose); pentaerythritols and structural derivatives thereof, such asmethylated, ethylated, acetate, ethoxylate, and propoxylate derivatives;and phenolic polyols such as 1,2,4 benzenetriol, 5-methylbenzene1,2,3-triol, 2,3,4-trihydroxybenzaldehyde, and3,4,5-trihydroxybenzamide.

As used herein, the term “tautomer” includes two or moreinterconvertable compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or vice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Where tautomerization is possible (e.g.,in solution), a chemical equilibrium of tautomers can be reached.Tautomerizations (i.e., the reaction providing a tautomeric pair) cancatalyzed by acid or base. “Prototropic tautomerization” or“proton-shift tautomerization” involves the migration of a protonaccompanied by changes in bond order. Exemplary tautomerizations includeketo-to-enol; amide-to-imide; lactam-to-lactim; enamine-to-imine; andenamine-to-(a different) enamine tautomerizations. A specific example ofketo-enol tautomerization is the interconversion of pentane-2,4-dioneand 4-hydroxypent-3-en-2-one tautomers. Another example oftautomerization is phenol-keto tautomerization. A specific example ofphenol-keto tautomerization is the interconversion of pyridin-4-ol andpyridin-4(1H)-one tautomers.

As used herein, the term “isomers” includes any and all geometricisomers and stereoisomers. For example, “isomers” include cis- andtrans-isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers,(D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixturesthereof.

Geometric isomers can be represented by the symbol

which denotes a bond that can be a single, double or triple bond asdescribed herein. Provided herein are various geometric isomers andmixtures thereof resulting from the arrangement of substituents around acarbon-carbon double bond or arrangement of substituents around acarbocyclic ring. Substituents around a carbon-carbon double bond aredesignated as being in the “Z” or “E” configuration wherein the terms“Z” and “E” are used in accordance with IUPAC standards. Unlessotherwise specified, structures depicting double bonds encompass boththe “E” and “Z” isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring can also be designated as “cis” or “trans.”The term “cis” represents substituents on the same side of the plane ofthe ring, and the term “trans” represents substituents on opposite sidesof the plane of the ring. Mixtures of compounds wherein the substituentsare disposed on both the same and opposite sides of plane of the ringare designated “cis/trans.”

As used herein, “polymorph” refers to a crystalline compound existing inmore than one crystalline form/structure. When polymorphism exists as aresult of difference in crystal packing it is called packingpolymorphism. Polymorphism can also result from the existence ofdifferent conformers of the same molecule in conformationalpolymorphism. In pseudopolymorphism the different crystal types are theresult of hydration or solvation.

As used herein, and unless otherwise specified, the term “solvate” meansa compound provided herein or a salt thereof, that further includes astoichiometric or non-stoichiometric amount of solvent bound bynon-covalent intermolecular forces. The solvate can be of a disclosedcompound or a pharmaceutically acceptable salt thereof. Where thesolvent is water, the solvate is a hydrate. Pharmaceutically acceptablesolvates and hydrates are complexes that, for example, can include about1 to about 100, or about 1 to about 10, or about 1 to about 2, about 3or about 4, solvent or water molecules. It will be understood that theterm “compound” as used herein encompasses the compound and solvates ofthe compound, as well as mixtures thereof.

The term “in vivo” refers to an event that takes place in a subject'sbody.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by 13C- or 14C-enriched carbonare within the scope of this disclosure.

The disclosure also embraces isotopically labeled compounds which areidentical to those recited herein, except that one or more atoms arereplaced by an atom having an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into disclosed compounds include, butare not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O,17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Certainisotopically-labeled disclosed compounds (e.g., those labeled with 3Hand 14C) are useful in compound and/or substrate tissue distributionassays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes canallow for ease of preparation and detectability. Further, substitutionwith heavier isotopes such as deuterium (i.e., 2H) can afford certaintherapeutic advantages resulting from greater metabolic stability (e.g.,increased in vivo half-life or reduced dosage requirements).Isotopically labeled disclosed compounds can generally be prepared bysubstituting an isotopically labeled reagent for a non-isotopicallylabeled reagent. In some embodiments, provided herein are compounds thatcan also contain unnatural proportions of atomic isotopes at one or moreof atoms that constitute such compounds. All isotopic variations of thecompounds as disclosed herein, whether radioactive or not, areencompassed within the scope of the present disclosure.

The term “in vitro” refers to an event that takes places outside of asubject's body. For example, an in vitro assay encompasses any assayconducted outside of a subject. In vitro assays encompass cell-basedassays in which cells, alive or dead, are employed. In vitro assays alsoencompass a cell-free assay in which no intact cells are employed.

“Pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” includes any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents and the like. The use of such media and agents forpharmaceutically active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions as disclosedherein is contemplated. Supplementary active ingredients can also beincorporated into the pharmaceutical compositions.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while apatient is suffering from the specified disease or disorder, whichreduces the severity of the disease or disorder, or retards or slows theprogression of the disease or disorder. As used herein, the terms“treatment”, “treating”, “palliating” and “ameliorating” are usedinterchangeably herein. These terms refer to an approach for obtainingbeneficial or desired results including, but not limited to, therapeuticbenefit and/or a prophylactic benefit. By therapeutic benefit is meanteradication or amelioration of the underlying disorder being treated.Also, a therapeutic benefit is achieved with the eradication oramelioration of one or more of the physiological symptoms associatedwith the underlying disorder such that an improvement is observed in thepatient, notwithstanding that the patient can still be afflicted withthe underlying disorder.

As used herein, and unless otherwise specified, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms thereof. The terms “prevent,” “preventing” and “prevention”contemplate an action that occurs before a patient begins to suffer fromthe specified disease or disorder, which inhibits or reduces theseverity of the disease or disorder.

As used herein, and unless otherwise indicated, the terms “manage,”“managing” and “management” encompass preventing the recurrence of thespecified disease or disorder in a patient who has already suffered fromthe disease or disorder, and/or lengthening the time that a patient whohas suffered from the disease or disorder remains in remission. Theterms encompass modulating the threshold, development and/or duration ofthe disease or disorder, or changing the way that a patient responds tothe disease or disorder.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent. The therapeutically effective amount can vary depending upon theintended application (in vitro or in vivo), or the subject and diseasecondition being treated, e.g., the weight and age of the subject, theseverity of the disease condition, the manner of administration and thelike, which can readily be determined by one of ordinary skill in theart. The term also applies to a dose that will induce a particularresponse in target cells, e.g., reduction of platelet adhesion and/orcell migration. The specific dose will vary depending on, for example,the particular compounds chosen, the dosing regimen to be followed,whether it is administered in combination with other agents, timing ofadministration, the tissue to which it is administered, and the physicaldelivery system in which it is carried.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the disease. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent. For prophylactic benefit, the pharmaceuticalcompositions can be administered to a patient at risk of developing aparticular disease, or to a patient reporting one or more of thephysiological symptoms of a disease, even though a diagnosis of thisdisease may not have been made.

2. Compounds

Without being limited by a particular theory, inhibitors of MAGL whichcontain at least one Lewis acidic boron head group, such as, forexample, a boronic acid, boronic ester, borinic acid or borinic esterhead group, are highly active antagonists of MAGL function.

In one embodiment, provided herein a compound of formula (I):

or a pharmaceutically acceptable form thereof;

wherein:

A is a 6 to 10 membered aryl, heteroaryl or heterocycle;

X is a covalent bond or —NR⁵;

R¹ and R² are each independently hydrogen, halogen, or an optionallysubstituted (C₁-C₆)alkyl;

R³ is —C(O)NH₂, —(CH₂)_(n)—NHR⁶ or —SO₂R⁷, and R⁴ is hydrogen; or

R³ and R⁴ taken together can form a 5 to 7 membered ring containing oneor more heteroatoms selected from N, S and O, wherein one or more carbonor sulfur atoms on the ring can optionally be substituted with one ormore oxo group;

R⁵ is hydrogen or —C(O)O—Y, wherein Y is an optionally substituted 6 to10 membered aryl or an optionally substituted (C₁-C₆)alkyl; R⁶ is anoptionally substituted (C₁-C₆)alkyl, —SO₂R⁸ or —C(O)R⁹;

R⁷, R⁸ and R⁹ are each independently an optionally substituted(C₁-C₆)alkyl or an optionally substituted amino; and

n is 0, 1, 2 or 3.

In one embodiment, provided herein a compound of formula (I):

or a pharmaceutically acceptable form thereof;

wherein:

A is a 6 to 10 membered aryl, heteroaryl or heterocycle;

X is a covalent bond or —NR⁵;

R¹ and R² are each independently hydrogen, halogen, or an optionallysubstituted (C₁-C₆)alkyl;

R³ is —C(O)NH₂, —(CH₂)_(n)—NHR⁶ or —SO₂R⁷, and R⁴ is hydrogen; or

R³ and R⁴ taken together can form a 5 to 7 membered ring containing oneor more heteroatoms selected from N, S and O, wherein one or more carbonor sulfur atoms on the ring can optionally be substituted with one ormore oxo group;

R⁵ is hydrogen or —C(O)O—Y, wherein Y is an optionally substituted 6 to10 membered aryl or an optionally substituted (C₁-C₆)alkyl;

R⁶ is an optionally substituted (C₁-C₆)alkyl, —SO₂R⁸ or —C(O)R⁹;

R⁷, R⁸ and R⁹ are each independently an optionally substituted(C₁-C₆)alkyl or an optionally substituted amino; and

n is 0, 1, 2 or 3;

wherein if R³ is —C(O)NH₂, then both R¹ and R² are not each hydrogen.

In certain embodiments, provided herein is a compound of formula (I),wherein A is 6-10 membered aryl and X is a covalent bond. In oneembodiment where A is 6-10 membered aryl, A is phenyl.

In one embodiment, provided herein is a compound of formula (II):

or a pharmaceutically acceptable form thereof,

wherein:

R¹⁰ and R¹¹ are each independently hydrogen, halogen or an optionallysubstituted (C₁-C₆)alkyl;

R¹² is —C(O)NH₂, —(CH₂)_(n)—NHR¹⁴ or —SO₂R¹⁵ and R¹³ is hydrogen; or

R¹² and R¹³ taken together can form a 5 to 7 membered ring containingone or more heteroatoms selected from N, S and O, wherein one or morecarbon or sulfur atoms on the ring can optionally be substituted withone or more oxo group;

R¹⁴ is an optionally substituted (C₁-C₆)alkyl, —SO₂R¹⁶ or —C(O)R¹⁷;

R¹⁵, R¹⁶ and R¹⁷ are each independently an optionally substituted(C₁-C₆)alkyl or an optionally substituted amino; and

n is 0, 1, 2 or 3.

In one embodiment, provided herein is a compound of formula (II):

or a pharmaceutically acceptable form thereof,

wherein:

R¹⁰ and R¹¹ are each independently hydrogen, halogen or an optionallysubstituted (C₁-C₆)alkyl;

R¹² is —C(O)NH₂, —(CH₂)_(n)—NHR¹⁴ or —SO₂R¹⁵ and R¹³ is hydrogen; or

R¹² and R¹³ taken together can form a 5 to 7 membered ring containingone or more heteroatoms selected from N, S and O, wherein one or morecarbon or sulfur atoms on the ring can optionally be substituted withone or more oxo group;

R¹⁴ is an optionally substituted (C₁-C₆)alkyl, —SO₂R¹⁶ or —C(O)R¹⁷;

R¹⁵, R¹⁶ and R¹⁷ are each independently an optionally substituted(C₁-C₆)alkyl or an optionally substituted amino; and

n is 0, 1, 2 or 3;

wherein if R¹² is —C(O)NH₂, then both R¹⁰ and R¹¹ are not each hydrogen.

In one embodiment, R¹⁰ and R¹¹ are each hydrogen. In another embodiment,R¹⁰ is halogen or an optionally substituted (C₁-C₆)alkyl, and R¹¹ ishydrogen.

In another embodiment, R¹⁰ is a halogen. In one embodiment, R¹⁰ is F,Cl, Br or I. In one embodiment, R¹⁰ is F.

In another embodiment, R¹⁰ is an optionally substituted (C₁-C₆)alkyl. Inone embodiment, R¹⁰ is an optionally substituted methyl, ethyl orpropyl. In another embodiment, R¹⁰ is optionally substituted methyl. Inone embodiment, R¹⁰ is methyl substituted with one or more halogen. Inone embodiment, R¹⁰ is methyl substituted with one or more F. In oneembodiment, R¹⁰ is —CF₃.

In one embodiment, R¹⁰ is halogen or an optionally substituted(C₁-C₆)alkyl, and R¹⁰ is para to the —B(OH)₂ group. In anotherembodiment, R¹⁰ is halogen or an optionally substituted (C₁-C₆)alkyl,and R¹⁰ is meta to the —B(OH)₂ group. In yet another embodiment, R¹⁰ ishalogen or an optionally substituted (C₁-C₆)alkyl, and R¹⁰ is ortho tothe —B(OH)₂ group and is ortho to the phenyl ring to which R¹² and R¹³are attached. In yet another embodiment, R¹⁰ is halogen or an optionallysubstituted (C₁-C₆)alkyl, and R¹⁰ is ortho to the —B(OH)₂ group and ispara to the phenyl ring to which R¹² and R¹³ are attached.

In one embodiment, R¹² is —C(O)NH₂.

In another embodiment, R¹² is —(CH₂)_(n)—NHR¹⁴. In one embodiment whereR¹² is —(CH₂)_(n)—NHR¹⁴, R¹⁴ is an optionally substituted (C₁-C₆)alkyl.

In another embodiment where R¹² is —(CH₂)_(n)—NHR¹⁴, R¹⁴ is —SO₂R¹⁶. Inone embodiment where R¹² is —(CH₂)_(n)—NHR¹⁴ and R¹⁴ is —SO₂R¹⁶, R¹⁶ isan optionally substituted (C₁-C₆)alkyl. In one embodiment, R¹⁶ ismethyl. In another embodiment, R¹⁶ is cyclopropyl. In another embodimentwhere R¹² is —(CH₂)_(n)—NHR¹⁴ and R¹⁴ is —SO₂R¹⁶, R¹⁶ is an optionallysubstituted amino.

In another embodiment where R¹² is —(CH₂)_(n)—NHR¹⁴, R¹⁴ is —C(O)R¹⁷. Inone embodiment where R¹² is —(CH₂)_(n)—NHR¹⁴ and R¹⁴ is —C(O)R¹⁷, R¹⁷ isan optionally substituted (C₁-C₆)alkyl. In one embodiment, R¹⁷ ismethyl. In another embodiment where R¹² is —(CH₂)_(n)—NHR¹⁴ and R¹⁴ is—C(O)R¹⁷, R¹⁷ is an optionally substituted amino. In one embodiment, R¹⁷is unsubstituted amino.

In another embodiment, R¹² is —SO₂R¹⁵. In one embodiment, R¹² is anoptionally substituted (C₁-C₆)alkyl. In another embodiment, R¹² is anoptionally substituted amino. In one embodiment, R¹² is unsubstitutedamino.

In one embodiment, R¹² is ortho to the covalent bond connecting the twophenyl rings. In another embodiment, R¹² is meta to the covalent bondconnecting the two phenyl rings. In yet another embodiment, R¹² is parato the covalent bond connecting the two phenyl rings.

In one embodiment, R¹² and R¹³ together form a 5 membered ring. Inanother embodiment, the 5 membered ring contains an unsubstituted N atom(e.g., an amine or an amide). In another embodiment, the 5 membered ringcontains an optionally substituted S atom and an unsubstituted N atom inadjacent positions on the ring (e.g., a sulfonamide). In anotherembodiment, one or more of the carbon atoms in the 5 membered ring aresubstituted with one or more oxo groups. In another embodiment whereinthe 5 membered ring contains an S atom, the sulfur is substituted withone or more oxo groups. In one embodiment, the 5 membered ring containsN, S and O atoms.

In one embodiment, R¹² and R¹³ together form a 6 membered ring. Inanother embodiment, the 6 membered ring contains an unsubstituted N(e.g., an amine or an amide). In another embodiment, the 6 membered ringcontains an optionally substituted S atom and an unsubstituted N atom inadjacent positions on the ring (e.g., a sulfonamide). In anotherembodiment, one or more of the carbon atoms in the 6 membered ring aresubstituted with one or more oxo groups. In another embodiment whereinthe 6 membered ring contains an S atom, the sulfur is substituted withone or more oxo groups. In one embodiment, the 6 membered ring containsN, S and O atoms.

In one embodiment, R¹² and R¹³ together form a 7 membered ring. Inanother embodiment, the 7 membered ring contains an unsubstituted N(e.g., an amine or an amide). In another embodiment, the 7 membered ringcontains an optionally substituted S atom and an unsubstituted N atom inadjacent positions on the ring (e.g., a sulfonamide). In anotherembodiment, one or more of the carbon atoms in the 7 membered ring aresubstituted with one or more oxo groups. In another embodiment whereinthe 7 membered ring contains an S atom, the sulfur is substituted withone or more oxo groups. In one embodiment, the 7 membered ring containsN, S and O atoms.

In one embodiment, provided herein is a compound of formula (II′):

or a pharmaceutically acceptable form thereof, wherein:

R¹⁰ is halogen or an optionally substituted (C₁-C₆)alkyl;

R¹¹ is hydrogen, halogen or an optionally substituted (C₁-C₆)alkyl;

R¹² is —C(O)NH₂, —(CH₂)_(n)—NHR¹⁴ or —SO₂R¹⁵ and R¹³ is hydrogen; or

R¹² and R¹³ taken together can form a 5 to 7 membered ring containingone or more heteroatoms selected from N, S and O, wherein one or morecarbon or sulfur atoms on the ring can optionally be substituted withone or more oxo group;

R¹⁴ is an optionally substituted (C₁-C₆)alkyl, —SO₂R¹⁶ or —C(O)R¹⁷;

R¹⁵, R¹⁶ and R¹⁷ are each independently an optionally substituted(C₁-C₆)alkyl or an optionally substituted amino; and

n is 0, 1, 2 or 3.

Also provided herein are all of the combinations of R¹⁰-R¹⁷ and nprovided above.

Exemplary compounds include, but are not limited to:

or a pharmaceutically acceptable form thereof.

In another embodiment, provided herein is a compound of formula (I),wherein A is 6-10 membered aryl; X is NR⁵; and R² and R⁴ are eachhydrogen. In one embodiment where A is 6-10 membered aryl, A is phenyl.

In one embodiment, provided herein is a compound of formula (III):

or a pharmaceutically acceptable form thereof,

wherein:

R¹⁸ is hydrogen, halogen, or an optionally substituted (C₁-C₆)alkyl;

R¹⁹ is hydrogen or —C(O)O—Y, wherein Y is an optionally substituted 6 to10 membered aryl or an optionally substituted (C₁-C₆)alkyl;

R²⁰ is hydrogen, —C(O)NH₂, —(CH₂)_(n)—NHR²¹ or —SO₂R²²;

R²¹ is an optionally substituted (C₁-C₆)alkyl, —SO₂R²³ or —C(O)R²⁴;

R²², R²³ and R²⁴ are each independently an optionally substituted(C₁-C₆)alkyl or an optionally substituted amino; and

n is 0, 1, 2 or 3.

In one embodiment, R¹⁸ is hydrogen. In another embodiment, R¹⁸ ishalogen. In another embodiment, R¹⁸ is an optionally substituted(C₁-C₆)alkyl.

In one embodiment, R¹⁹ is hydrogen. In another embodiment, R¹⁹ is—C(O)O—Y, wherein Y is an optionally substituted 6 to 10 membered aryl.In one particular embodiment, Y is phenyl. In another embodiment, R¹⁹ is—C(O)O—Y, wherein Y is t-butyl.

R²⁰ is —C(O)NH₂. In another embodiment, R²⁰ is —(CH₂)_(n)—NHR²¹. Inanother embodiment, R²⁰ is —SO₂R²².

In one embodiment, R²⁰ is hydrogen.

In one embodiment, R²¹ is an optionally substituted (C₁-C₆)alkyl. Inanother embodiment, R²¹ is —SO₂R²³. In another embodiment, R²¹ is—C(O)R²⁴.

In one embodiment, R²² is an optionally substituted (C₁-C₆)alkyl. Inanother embodiment, R²² is an optionally substituted amino.

In one embodiment, R²³ is an optionally substituted (C₁-C₆)alkyl. Inanother embodiment, R²³ is an optionally substituted amino.

In one embodiment, R²⁴ is an optionally substituted (C₁-C₆)alkyl. Inanother embodiment, R²⁴ is an optionally substituted amino.

In one embodiment, R¹⁸ and R¹⁹ are both hydrogen.

Also provided herein are all of the combinations of R¹⁸-R²⁴ and nprovided above.

Exemplary compounds include, but are not limited to:

or a pharmaceutically acceptable form thereof.

In another embodiment, provided herein is a is a compound of formula(I), wherein A is 6-10 membered heteroaryl; X is a covalent bond; and R²and R⁴ are each hydrogen. In one embodiment where A is 6-10 memberedheteroaryl, A is benzthiazole.

In one embodiment, provided herein is a compound of formula (IV):

or a pharmaceutically acceptable form thereof,

wherein:

R²⁵ is hydrogen, halogen, or an optionally substituted (C₁-C₆)alkyl;

R²⁶ is hydrogen, —C(O)NH₂, —(CH₂)_(n)—NHR²⁷ or —SO₂R²⁸;

R²⁷ is an optionally substituted (C₁-C₆)alkyl, —SO₂R²⁹ or —C(O)R³⁰;

R²⁸, R²⁹ and R³⁰ are each independently an optionally substituted(C₁-C₆)alkyl or an optionally substituted amino; and

n is 0, 1, 2 or 3.

In one embodiment, R²⁵ is hydrogen. In another embodiment, R²⁵ ishalogen. In another embodiment, R²⁵ is an optionally substituted(C₁-C₆)alkyl.

In one embodiment, R²⁶ is hydrogen. In another embodiment, R²⁶ is—C(O)NH₂. In another embodiment, R²⁶ is —(CH₂)_(n)—NHR²⁷. In anotherembodiment, R²⁶ is —SO₂R²⁸.

In one embodiment, R²⁷ is an optionally substituted (C₁-C₆)alkyl. Inanother embodiment, R²⁷ is —SO₂R²⁹. In another embodiment, R²⁷ is—C(O)R³⁰.

In one embodiment, R²⁸ is an optionally substituted (C₁-C₆)alkyl. Inanother embodiment, R²⁸ is an optionally substituted amino.

In one embodiment, R²⁹ is an optionally substituted (C₁-C₆)alkyl. Inanother embodiment, R²⁹ is an optionally substituted amino.

In one embodiment, R³⁰ is an optionally substituted (C₁-C₆)alkyl. Inanother embodiment, R³⁰ is an optionally substituted amino.

In one embodiment, R²⁵ is halogen, (e.g., fluoro). In one embodiment,R²⁶ is hydrogen.

Also provided herein are all of the combinations of R²⁵-R³⁰ and nprovided above.

Exemplary compounds include, but are not limited to:

or a pharmaceutically acceptable form thereof.

3. Pharmaceutical Compositions and Formulations

In some embodiments, provided herein are pharmaceutical compositionscomprising one or more compounds as disclosed herein, or apharmaceutically acceptable form thereof (e.g., pharmaceuticallyacceptable salts, isomers, prodrugs, and isotopically labeledderivatives), and one or more pharmaceutically acceptable excipientscarriers, including, but not limited to, inert solid diluents andfillers, diluents, including sterile aqueous solution and variousorganic solvents, permeation enhancers, solubilizers and adjuvants.

A pharmaceutically acceptable excipient, as used herein, includes, butis not limited to, any and all solvents, diluents, or other liquidvehicle, dispersion or suspension aids, surface active agents, isotonicagents, thickening or emulsifying agents, preservatives, solid binders,lubricants, coatings, antibacterial and antifungal agents, isotonic andabsorption delaying agents and the like, as suited to a particulardosage form. In this disclosure, the terms “carrier” and “excipient” areused interchangeably unless otherwise specified. For example,Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin(Mack Publishing Co., Easton, Pa., 1980) discloses various carriers usedin formulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds providedherein, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of the disclosure.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition.Proper fluidity can be maintained, for example, by the use of coatingmaterials, such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

Pharmaceutical compositions can be specially formulated foradministration in solid or liquid form, including those adapted for thefollowing: oral administration, for example, drenches (aqueous ornon-aqueous solutions or suspensions), tablets (e.g., those targeted forbuccal, sublingual, and systemic absorption), capsules, boluses,powders, granules, pastes for application to the tongue, andintraduodenal routes; parenteral administration, including intravenous,intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion as, for example, a sterile solution orsuspension, or sustained-release formulation; topical application, forexample, as a cream, ointment, or a controlled-release patch or sprayapplied to the skin; intravaginally or intrarectally, for example, as apessary, cream, stent or foam; sublingually; ocularly; pulmonarily;local delivery by catheter or stent; intrathecally, or nasally.

These compositions can also contain adjuvants such as preservatives,wetting agents, emulsifying agents, dispersing agents, lubricants,and/or antioxidants. Prevention of the action of microorganisms upon thecompounds described herein can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. In some embodiments,isotonic agents, such as sugars, sodium chloride, and the like can beincluded in the compositions. In addition, prolonged absorption of theinjectable pharmaceutical form can be brought about by the inclusion ofagents which delay absorption such as aluminum monostearate and gelatin.

The formulations of the pharmaceutical compositions described herein canbe prepared by any method known or hereafter developed in the art ofpharmacology. In general, such preparatory methods include the step ofbringing the active ingredient into association with a carrier and/orone or more other accessory ingredients, and then, if necessary and/ordesirable, shaping and/or packaging the product into a desired single-or multi-dose unit. See, e.g., Anderson, Philip O.; Knoben, James E.;Troutman, William G, eds., Handbook of Clinical Drug Data, TenthEdition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of DrugAction, Third Edition, Churchill Livingston, N.Y., 1990; Katzung, ed.,Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg;Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics,Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences,20th Ed., Lippincott Williams & Wilkins, 2000; Martindale, The ExtraPharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London,1999); all of which are incorporated by reference herein in theirentirety. Except insofar as any conventional excipient medium isincompatible with the compounds provided herein, such as by producingany undesirable biological effect or otherwise interacting in adeleterious manner with any other component(s) of the pharmaceuticallyacceptable composition, the excipient's use is contemplated to be withinthe scope of this disclosure.

A pharmaceutical composition provided herein can be prepared, packaged,and/or sold in bulk, as a single unit dose, and/or as a plurality ofsingle unit doses. As used herein, a “unit dose” is discrete amount ofthe pharmaceutical composition comprising a predetermined amount of theactive ingredient. The amount of the active ingredient is generallyequal to the dosage of the active ingredient which would be administeredto a subject and/or a convenient fraction of such a dosage such as, forexample, one-half or one-third of such a dosage.

The relative amounts of the active ingredient, the pharmaceuticallyacceptable carrier, and/or any additional ingredients in apharmaceutical composition provided herein will vary, depending upon theidentity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.By way of example, the composition can comprise between about 0.1% andabout 100% (w/w) active ingredient.

In some embodiments, the concentration of one or more of the compoundsprovided in the disclosed pharmaceutical compositions is less than about100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%,about 30%, about 20%, about 19%, about 18%, about 17%, about 16%, about15%, about 14%, about 13%, about 12%, about 11%, about 10%, about 9%,about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%,about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%,about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%,about 0.0002%, or about 0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of one or more of the compoundsas disclosed herein is greater than about 90%, about 80%, about 70%,about 60%, about 50%, about 40%, about 30%, about 20%, about 19.75%,about 19.50%, about 19.25%, about 19%, about 18.75%, about 18.50%, about18.25%, about 18%, about 17.75%, about 17.50%, about 17.25%, about 17%,about 16.75%, about 16.50%, about 16.25%, about 16%, about 15.75%, about15.50%, about 15.25%, about 15%, about 14.75%, about 14.50%, about14.25%, about 14%, about 13.75%, about 13.50%, about 13.25%, about 13%,about 12.75%, about 12.50%, about 12.25%, about 12%, about 11.75%, about11.50%, about 11.25%, about 11%, about 10.75%, about 10.50%, about10.25%, about 10%, about 9.75%, about 9.50%, about 9.25%, about 9%,about 8.75%, about 8.50%, about 8.25%, about 8%, about 7.75%, about7.50%, about 7.25%, about 7%, about 6.75%, about 6.50%, about 6.25%,about 6%, about 5.75%, about 5.50%, about 5.25%, about 5%, about 4.75%,about 4.50%, about 4.25%, about 4%, about 3.75%, about 3.50%, about3.25%, about 3%, about 2.75%, about 2.50%, about 2.25%, about 2%, about1.75%, about 1.50%, about 1.25%, about 1%, about 0.5%, about 0.4%, about0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%,about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about0.0009%, about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%,about 0.0004%, about 0.0003%, about 0.0002%, or about 0.0001% w/w, w/v,or v/v.

In some embodiments, the concentration of one or more of the compoundsas disclosed herein is in the range from approximately 0.0001% toapproximately 50%, approximately 0.001% to approximately 40%,approximately 0.01% to approximately 30%, approximately 0.02% toapproximately 29%, approximately 0.03% to approximately 28%,approximately 0.04% to approximately 27%, approximately 0.05% toapproximately 26%, approximately 0.06% to approximately 25%,approximately 0.07% to approximately 24%, approximately 0.08% toapproximately 23%, approximately 0.09% to approximately 22%,approximately 0.1% to approximately 21%, approximately 0.2% toapproximately 20%, approximately 0.3% to approximately 19%,approximately 0.4% to approximately 18%, approximately 0.5% toapproximately 17%, approximately 0.6% to approximately 16%,approximately 0.7% to approximately 15%, approximately 0.8% toapproximately 14%, approximately 0.9% to approximately 12%,approximately 1% to approximately 10% w/w, w/v or v/v. v/v.

In some embodiments, the concentration of one or more of the compoundsas disclosed herein is in the range from approximately 0.001% toapproximately 10%, approximately 0.01% to approximately 5%,approximately 0.02% to approximately 4.5%, approximately 0.03% toapproximately 4%, approximately 0.04% to approximately 3.5%,approximately 0.05% to approximately 3%, approximately 0.06% toapproximately 2.5%, approximately 0.07% to approximately 2%,approximately 0.08% to approximately 1.5%, approximately 0.09% toapproximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v orv/v.

In some embodiments, the amount of one or more of the compounds asdisclosed herein is equal to or less than about 10 g, about 9.5 g, about9.0 g, about 8.5 g, about 8.0 g, about 7.5 g, about 7.0 g, about 6.5 g,about 6.0 g, about 5.5 g, about 5.0 g, about 4.5 g, about 4.0 g, about3.5 g, about 3.0 g, about 2.5 g, about 2.0 g, about 1.5 g, about 1.0 g,about 0.95 g, about 0.9 g, about 0.85 g, about 0.8 g, about 0.75 g,about 0.7 g, about 0.65 g, about 0.6 g, about 0.55 g, about 0.5 g, about0.45 g, about 0.4 g, about 0.35 g, about 0.3 g, about 0.25 g, about 0.2g, about 0.15 g, about 0.1 g, about 0.09 g, about 0.08 g, about 0.07 g,about 0.06 g, about 0.05 g, about 0.04 g, about 0.03 g, about 0.02 g,about 0.01 g, about 0.009 g, about 0.008 g, about 0.007 g, about 0.006g, about 0.005 g, about 0.004 g, about 0.003 g, about 0.002 g, about0.001 g, about 0.0009 g, about 0.0008 g, about 0.0007 g, about 0.0006 g,about 0.0005 g, about 0.0004 g, about 0.0003 g, about 0.0002 g, or about0.0001 g.

In some embodiments, the amount of one or more of the compounds asdisclosed herein is more than about 0.0001 g, about 0.0002 g, about0.0003 g, about 0.0004 g, about 0.0005 g, about 0.0006 g, about 0.0007g, about 0.0008 g, about 0.0009 g, about 0.001 g, about 0.0015 g, about0.002 g, about 0.0025 g, about 0.003 g, about 0.0035 g, about 0.004 g,about 0.0045 g, about 0.005 g, about 0.0055 g, about 0.006 g, about0.0065 g, about 0.007 g, about 0.0075 g, about 0.008 g, about 0.0085 g,about 0.009 g, about 0.0095 g, about 0.01 g, about 0.015 g, about 0.02g, about 0.025 g, about 0.03 g, about 0.035 g, about 0.04 g, about 0.045g, about 0.05 g, about 0.055 g, about 0.06 g, about 0.065 g, about 0.07g, about 0.075 g, about 0.08 g, about 0.085 g, about 0.09 g, about 0.095g, about 0.1 g, about 0.15 g, about 0.2 g, about 0.25 g, about 0.3 g,about 0.35 g, about 0.4 g, about 0.45 g, about 0.5 g, about 0.55 g,about 0.6 g, about 0.65 g, about 0.7 g, about 0.75 g, about 0.8 g, about0.85 g, about 0.9 g, about 0.95 g, about 1 g, about 1.5 g, about 2 g,about 2.5, about 3 g, about 3.5, about 4 g, about 4.5 g, about 5 g,about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g,about 8.5 g, about 9 g, about 9.5 g, or about 10 g.

In some embodiments, the amount of one or more of the compounds asdisclosed herein is in the range of about 0.0001-about 10 g, about0.0005-about 9 g, about 0.001-about 8 g, about 0.005-about 7 g, about0.01-about 6 g, about 0.05-about 5 g, about 0.1-about 4 g, about0.5-about 4 g, or about 1-about 3 g.

A compound described herein can be delivered in the form ofpharmaceutically acceptable compositions which comprise atherapeutically effective amount of one or more compounds describedherein and/or one or more additional therapeutic agents, formulatedtogether with one or more pharmaceutically acceptable excipients. Insome instances, the compound described herein and the additionaltherapeutic agent are administered in separate pharmaceuticalcompositions and can (e.g., because of different physical and/orchemical characteristics) be administered by different routes (e.g., onetherapeutic is administered orally, while the other is administeredintravenously). In other instances, the compound described herein andthe additional therapeutic agent can be administered separately, but viathe same route (e.g., both orally or both intravenously). In still otherinstances, the compound described herein and the additional therapeuticagent can be administered in the same pharmaceutical composition.

The selected dosage level will depend upon a variety of factorsincluding, for example, the activity of the particular compoundemployed, the route of administration, the time of administration, therate of excretion or metabolism of the particular compound beingemployed, the rate and extent of absorption, the duration of thetreatment, other drugs, compounds and/or materials used in combinationwith the particular compound employed, the age, sex, weight, condition,general health and prior medical history of the patient being treated,and like factors well known in the medical arts.

In general, a suitable daily dose of a compound described herein will bethat amount of the compound which, in some embodiments, can be thelowest dose effective to produce a therapeutic effect. Such an effectivedose will generally depend upon the factors described above. Generally,doses of the compounds described herein for a patient, when used for theindicated effects, will range from about 0.0001 mg to about 100 mg perday, or about 0.001 mg to about 100 mg per day, or about 0.01 mg toabout 100 mg per day, or about 0.1 mg to about 100 mg per day, or about0.0001 mg to about 500 mg per day, or about 0.001 mg to about 500 mg perday, or about 0.01 mg to 1000 mg, or about 0.01 mg to about 500 mg perday, or about 0.1 mg to about 500 mg per day, or about about 1 mg to 50mg per day, or about 5 mg to 40 mg. An exemplary dosage is about 10 to30 mg per day. In some embodiments, for a 70 kg human, a suitable dosewould be about 0.05 to about 7 g/day, such as about 0.05 to about 2.5g/day. Actual dosage levels of the active ingredients in thepharmaceutical compositions described herein can be varied so as toobtain an amount of the active ingredient which is effective to achievethe desired therapeutic response for a particular patient, composition,and mode of administration, without being toxic to the patient. In someinstances, dosage levels below the lower limit of the aforesaid rangecan be more than adequate, while in other cases still larger doses canbe employed without causing any harmful side effect, e.g., by dividingsuch larger doses into several small doses for administration throughoutthe day.

In some embodiments, the compounds can be administered daily, everyother day, three times a week, twice a week, weekly, or bi-weekly. Thedosing schedule can include a “drug holiday,” i.e., the drug can beadministered for two weeks on, one week off, or three weeks on, one weekoff, or four weeks on, one week off, etc., or continuously, without adrug holiday. The compounds can be administered orally, intravenously,intraperitoneally, topically, transdermally, intramuscularly,subcutaneously, intranasally, sublingually, or by any other route.

In some embodiments, a compound as provided herein is administered inmultiple doses. Dosing can be about once, about twice, about threetimes, about four times, about five times, about six times, or more thanabout six times per day. Dosing can be about once a month, about onceevery two weeks, about once a week, or about once every other day. Inanother embodiment, a compound as disclosed herein and another agent areadministered together about once per day to about 6 times per day. Inanother embodiment, the administration of a compound as provided hereinand an agent continues for less than about 7 days. In yet anotherembodiment, the administration continues for more than about 6, about10, about 14, about 28 days, about two months, about six months, orabout one year. In some cases, continuous dosing is achieved andmaintained as long as necessary.

Administration of the pharmaceutical compositions as disclosed hereincan continue as long as necessary. In some embodiments, an agent asdisclosed herein is administered for more than about 1, about 2, about3, about 4, about 5, about 6, about 7, about 14, or about 28 days. Insome embodiments, an agent as disclosed herein is administered for lessthan about 28, about 14, about 7, about 6, about 5, about 4, about 3,about 2, or about 1 day. In some embodiments, an agent as disclosedherein is administered chronically on an ongoing basis, e.g., for thetreatment of chronic effects.

Since the compounds described herein can be administered in combinationwith other treatments, the doses of each agent or therapy can be lowerthan the corresponding dose for single-agent therapy. The dose forsingle-agent therapy can range from, for example, about 0.0001 to about200 mg, or about 0.001 to about 100 mg, or about 0.01 to about 100 mg,or about 0.1 to about 100 mg, or about 1 to about 50 mg per kilogram ofbody weight per day.

When a compound provided herein, is administered in a pharmaceuticalcomposition that comprises one or more agents, and the agent has ashorter half-life than the compound provided herein unit dose forms ofthe agent and the compound provided herein can be adjusted accordingly.

In some embodiments, the pharmaceutically acceptable excipient presentin an exemplary pharmaceutical composition is at least about 95%, about96%, about 97%, about 98%, about 99%, or about 100% pure. In someembodiments, the excipient is approved for use in humans and forveterinary use. In some embodiments, the excipient is approved by UnitedStates Food and Drug Administration. In some embodiments, the excipientis of pharmaceutical grade. In some embodiments, the excipient meets thestandards of the United States Pharmacopoeia (USP), the EuropeanPharmacopoeia (EP), the British Pharmacopoeia, and/or the InternationalPharmacopoeia.

Pharmaceutically acceptable excipients used in the manufacture ofpharmaceutical compositions include, but are not limited to, inertdiluents, dispersing and/or granulating agents, surface active agentsand/or emulsifiers, disintegrating agents, binding agents,preservatives, buffering agents, lubricating agents, and/or oils. Suchexcipients can optionally be included in the formulations. Excipientssuch as cocoa butter and suppository waxes, coloring agents, coatingagents, sweetening, flavoring, and perfuming agents can be present inthe composition, according to the judgment of the formulator.

Exemplary diluents include, but are not limited to, calcium carbonate,sodium carbonate, calcium phosphate, dicalcium phosphate, calciumsulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose,cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol,inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc.,and combinations thereof

Exemplary granulating and/or dispersing agents include, but are notlimited to, potato starch, corn starch, tapioca starch, sodium starchglycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite,cellulose and wood products, natural sponge, cation-exchange resins,calcium carbonate, silicates, sodium carbonate, cross-linkedpoly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch(sodium starch glycolate), carboxymethyl cellulose, cross-linked sodiumcarboxymethyl cellulose (croscarmellose), methylcellulose,pregelatinized starch (starch 1500), microcrystalline starch, waterinsoluble starch, calcium carboxymethyl cellulose, magnesium aluminumsilicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds,etc., and combinations thereof

Exemplary surface active agents and/or emulsifiers include, but are notlimited to, natural emulsifiers (e.g. acacia, agar, alginic acid, sodiumalginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin,egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidalclays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminumsilicate]), long chain amino acid derivatives, high molecular weightalcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetinmonostearate, ethylene glycol distearate, glyceryl monostearate, andpropylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.carboxy polymethylene, polyacrylic acid, acrylic acid polymer, andcarboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.carboxymethylcellulose sodium, powdered cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylenesorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60],polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate[Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span65], glyceryl monooleate, sorbitan monooleate [Span 80]),polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45],polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil,polyoxymethylene stearate, and Solutol), sucrose fatty acid esters,polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethyleneethers, (e.g. polyoxyethylene lauryl ether [Brij 30]),poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamineoleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188,cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride,docusate sodium, etc. and/or combinations thereof.

Exemplary binding agents include, but are not limited to, starch (e.g.cornstarch and starch paste); gelatin; sugars (e.g. sucrose, glucose,dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.); naturaland synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss,panwar gum, ghatti gum, mucilage of isapol husks,carboxymethylcellulose, methylcellulose, ethylcellulose,hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate,poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larcharabogalactan); alginates; polyethylene oxide; polyethylene glycol;inorganic calcium salts; silicic acid; polymethacrylates; waxes; water;alcohol; and combinations thereof

Exemplary preservatives can include, but are not limited to,antioxidants, chelating agents, antimicrobial preservatives, antifungalpreservatives, alcohol preservatives, acidic preservatives, and otherpreservatives. Exemplary antioxidants include, but are not limited to,alpha tocopherol, ascorbic acid, acorbyl palmitate, butylatedhydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassiummetabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodiumbisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelatingagents include, but are not limited to, ethylenediaminetetraacetic acid(EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate,edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate,tartaric acid, and trisodium edetate. Exemplary antimicrobialpreservatives include, but are not limited to, benzalkonium chloride,benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal. Exemplary antifungal preservativesinclude, but are not limited to, butyl paraben, methyl paraben, ethylparaben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassiumbenzoate, potassium sorbate, sodium benzoate, sodium propionate, andsorbic acid. Exemplary alcohol preservatives include, but are notlimited to, ethanol, polyethylene glycol, phenol, phenolic compounds,bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.Exemplary acidic preservatives include, but are not limited to, vitaminA, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid,dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Otherpreservatives include, but are not limited to, tocopherol, tocopherolacetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA),butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate(SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus,Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, andEuxyl. In certain embodiments, the preservative is an anti-oxidant. Inother embodiments, the preservative is a chelating agent.

Exemplary buffering agents include, but are not limited to, citratebuffer solutions, acetate buffer solutions, phosphate buffer solutions,ammonium chloride, calcium carbonate, calcium chloride, calcium citrate,calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconicacid, calcium glycerophosphate, calcium lactate, propanoic acid, calciumlevulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid,tribasic calcium phosphate, calcium hydroxide phosphate, potassiumacetate, potassium chloride, potassium gluconate, potassium mixtures,dibasic potassium phosphate, monobasic potassium phosphate, potassiumphosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride,sodium citrate, sodium lactate, dibasic sodium phosphate, monobasicsodium phosphate, sodium phosphate mixtures, tromethamine, magnesiumhydroxide, aluminum hydroxide, alginic acid, pyrogen-free water,isotonic saline, Ringer's solution, ethyl alcohol, etc., andcombinations thereof

Exemplary lubricating agents include, but are not limited to, magnesiumstearate, calcium stearate, zinc stearate, ethyl oleate, ethyl laurate,agar, stearic acid, mineral oil, glycerin, sorbitol, mannitol, silica,talc, malt, glyceryl behanate, hydrogenated vegetable oils (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), polyethylene glycol, sodium benzoate, sodium acetate,sodium chloride, leucine, magnesium lauryl sulfate, sodium laurylsulfate, etc., and combinations thereof. Additional lubricants include,for example, a syloid silica gel, a coagulated aerosol of syntheticsilica, or mixtures thereof. A lubricant can optionally be added, in anamount of less than about 1 weight percent of the pharmaceuticalcomposition.

Exemplary oils include, but are not limited to, almond, apricot kernel,avocado, babassu, bergamot, black current seed, borage, cade, camomile,canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, codliver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose,fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop,isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon,litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink,nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel,peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary,safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, sheabutter, silicone, soybean, sunflower, tea tree, thistle, tsubaki,vetiver, walnut, and wheat germ oils. Exemplary oils include, but arenot limited to, butyl stearate, caprylic triglyceride, caprictriglyceride, cyclomethicone, diethyl sebacate, dimethicone 360,isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol,silicone oil, and combinations thereof

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants can be used in the pharmaceutical compositions as providedherein to provide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant can produce tablets which candisintegrate in the bottle. Too little can be insufficient fordisintegration to occur and can thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s) canbe used to form the dosage forms of the compounds disclosed herein. Theamount of disintegrant used can vary based upon the type of formulationand mode of administration, and can be readily discernible to those ofordinary skill in the art. About 0.5 to about 15 weight percent ofdisintegrant, or about 1 to about 5 weight percent of disintegrant, canbe used in the pharmaceutical composition. Disintegrants that can beused to form pharmaceutical compositions and dosage forms include, butare not limited to, agar-agar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,other starches, pre-gelatinized starch, other starches, clays, otheralgins, other celluloses, gums or mixtures thereof

Surfactants which can be used to form pharmaceutical compositions anddosage forms include, but are not limited to, hydrophilic surfactants,lipophilic surfactants, and mixtures thereof. That is, a mixture ofhydrophilic surfactants can be employed, a mixture of lipophilicsurfactants can be employed, or a mixture of at least one hydrophilicsurfactant and at least one lipophilic surfactant can be employed.

A suitable hydrophilic surfactant can generally have an HLB value of atleast about 10, while suitable lipophilic surfactants can generally havean HLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions. Hydrophilic surfactants are generally considered tobe those compounds having an HLB value greater than about 10, as well asanionic, cationic, or zwitterionic compounds for which the HLB scale isnot generally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are compounds having an HLB value equal to or less thanabout 10. However, HLB value of a surfactant is merely a rough guidegenerally used to enable formulation of industrial, pharmaceutical andcosmetic emulsions.

Hydrophilic surfactants can be either ionic or non-ionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acylactylates; mono- and di-acetylated tartaricacid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof

Ionic surfactants can be the ionized forms of lecithin, lysolecithin,phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof

Hydrophilic non-ionic surfactants can include, but are not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of glycerides, vegetable oils, hydrogenated vegetable oils, fattyacids, and sterols; polyoxyethylene sterols, derivatives, and analoguesthereof; polyoxyethylated vitamins and derivatives thereof;polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof;polyethylene glycol sorbitan fatty acid esters and hydrophilictransesterification products of a polyol with at least one member oftriglycerides, vegetable oils, and hydrogenated vegetable oils. Thepolyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol,propylene glycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrosemonolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of glycerides, vegetable oils, hydrogenated vegetable oils, fattyacids and sterols; oil-soluble vitamins/vitamin derivatives; andmixtures thereof. Within this group, non-limiting examples of lipophilicsurfactants include, but are not limited to, glycerol fatty acid esters,propylene glycol fatty acid esters, and mixtures thereof, or arehydrophobic transesterification products of a polyol with at least onemember of vegetable oils, hydrogenated vegetable oils, andtriglycerides.

In one embodiment, the pharmaceutical composition can include asolubilizer to ensure good solubilization and/or dissolution of acompound as provided herein and to minimize precipitation of thecompound. This can be especially important for pharmaceuticalcompositions for non-oral use, e.g., pharmaceutical compositions forinjection. A solubilizer can also be added to increase the solubility ofthe hydrophilic drug and/or other components, such as surfactants, or tomaintain the pharmaceutical composition as a stable or homogeneoussolution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydroxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, 8-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers can also be used. Examples include, but are notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. In someembodiments, solubilizers include, but are not limited to, sorbitol,glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propyleneglycol.

The amount of solubilizer that can be included can vary. The amount of agiven solubilizer can be limited to a bioacceptable amount, which can bereadily determined by one of skill in the art. In some circumstances, itcan be advantageous to include amounts of solubilizers far in excess ofbioacceptable amounts, for example to maximize the concentration of thedrug, with excess solubilizer removed prior to providing thepharmaceutical composition to a subject using conventional techniques,such as distillation or evaporation. Thus, if present, the solubilizercan be in a weight ratio of about 10%, about 25%, about 50%, about 100%,or up to about 200% by weight, based on the combined weight of the drug,and other excipients. In some embodiments, very small amounts ofsolubilizer can also be used, such as about 5%, about 2%, about 1% oreven less. Typically, the solubilizer can be present in an amount ofabout 1% to about 100%, more typically about 5% to about 25% by weight.

In addition, an acid or a base can be incorporated into thepharmaceutical composition to facilitate processing, to enhancestability, or for other reasons. Non-limiting examples ofpharmaceutically acceptable bases include amino acids, amino acidesters, ammonium hydroxide, potassium hydroxide, sodium hydroxide,sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate,magnesium hydroxide, magnesium aluminum silicate, synthetic aluminumsilicate, synthetic hydrocalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamine, trimethylamine,tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable arebases that are salts of a pharmaceutically acceptable acid, such asacetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionicacid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinicacid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonicacid, uric acid, and the like. Salts of polyprotic acids, such as sodiumphosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphatecan also be used. When the base is a salt, the cation can be anyconvenient and pharmaceutically acceptable cation, such as ammonium,alkali metals, alkaline earth metals, and the like. Examples caninclude, but are not limited to, sodium, potassium, lithium, magnesium,calcium and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

Liquid dosage forms for oral and parenteral administration include, butare not limited to, pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups and elixirs. In additionto the active ingredients, the liquid dosage forms can comprise inertdiluents commonly used in the art such as, for example, water or othersolvents, solubilizing agents and emulsifiers such as ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethylformamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof. Besides inert diluents, the oral compositions caninclude adjuvants such as wetting agents, emulsifying and suspendingagents, sweetening, flavoring, and perfuming agents. In certainembodiments for parenteral administration, the conjugates are mixed withsolubilizing agents such as Cremophor, alcohols, oils, modified oils,glycols, polysorbates, cyclodextrins, polymers, and combinationsthereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Theforms in which the disclosed pharmaceutical compositions can beincorporated for administration by injection include, but are notlimited to, aqueous or oil suspensions, or emulsions, with sesame oil,corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol,dextrose, or a sterile aqueous solution, and similar pharmaceuticalvehicles. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilcan be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid are used in the preparation ofinjectables. Aqueous solutions in saline are also conventionally usedfor injection. Ethanol, glycerol, propylene glycol, liquid polyethyleneglycol, and the like (and suitable mixtures thereof), cyclodextrinderivatives, and vegetable oils can also be employed. The properfluidity can be maintained, for example, by the use of a coating, suchas lecithin, for the maintenance of the required particle size in thecase of dispersion and by the use of surfactants. The prevention of theaction of microorganisms can be brought about by various antibacterialand antifungal agents, for example, parabens, chlorobutanol, phenol,sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compound asdisclosed herein in the required amount in the appropriate solvent withvarious other ingredients as enumerated above, as appropriate, followedby filtered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the appropriateother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, certainmethods of preparation are vacuum-drying and freeze-drying techniqueswhich yield a powder of the active ingredient plus any additionalingredient from a previously sterile-filtered solution thereof.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, can depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates withsuitable non-irritating excipients or carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include, but are not limitedto, capsules, tablets, pills, powders, and granules. In such soliddosage forms, the active ingredient is mixed with at least one inert,pharmaceutically acceptable excipient or carrier such as sodium citrateor dicalcium phosphate and/or a) fillers or extenders such as starches,lactose, sucrose, glucose, mannitol, and silicic acid, b) binders suchas, for example, carboxymethylcellulose, alginates, gelatin,polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such asglycerol, d) disintegrating agents such as agar, calcium carbonate,potato or tapioca starch, alginic acid, certain silicates, and sodiumcarbonate, e) solution retarding agents such as paraffin, f) absorptionaccelerators such as quaternary ammonium compounds, g) wetting agentssuch as, for example, cetyl alcohol and glycerol monostearate, h)absorbents such as kaolin and bentonite clay, and i) lubricants such astalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof. In the case of capsules,tablets and pills, the dosage form can comprise buffering agents.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They can optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, or in somecases, in a certain part of the intestinal tract, optionally, in adelayed manner. Examples of embedding compositions which can be usedinclude polymeric substances and waxes. Solid compositions of a similartype can be employed as fillers in soft and hard-filled gelatin capsulesusing such excipients as lactose or milk sugar as well as high molecularweight polethylene glycols and the like.

The active ingredients can be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose or starch. Such dosage forms cancomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms can comprise bufferingagents. Examples of embedding compositions which can be used includepolymeric substances and waxes.

In some embodiments, provided herein are pharmaceutical compositions fororal administration containing a compound as disclosed herein, and apharmaceutical excipient suitable for oral administration. In someembodiments, the pharmaceutical composition can be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions suitable for oral administration can be presented asdiscrete dosage forms, such as capsules, cachets, or tablets, or liquidsor aerosol sprays each containing a predetermined amount of an activeingredient as a powder or in granules, a solution, or a suspension in anaqueous or non-aqueous liquid, an oil-in-water emulsion, or awater-in-oil liquid emulsion. Such dosage forms can be prepared by anyof the methods of pharmacy, but all methods include the step of bringingthe active ingredient into association with the carrier, whichconstitutes one or more ingredients. In general, the pharmaceuticalcompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into a givenpresentation. For example, a tablet can be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets can be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with an excipient such as, but not limited to, a binder, alubricant, an inert diluent, and/or a surface active or dispersingagent. Molded tablets can be made by molding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.

The present disclosure further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising an active ingredient, sincewater can facilitate the degradation of some compounds. For example,water can be added (e.g., about 5%) in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime Anhydrous pharmaceutical compositions and dosage forms can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. For example, pharmaceuticalcompositions and dosage forms which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition can be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous pharmaceuticalcompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

Dosage forms for topical and/or transdermal administration of a compoundprovided herein can include, but are not limited to, ointments, pastes,creams, lotions, gels, powders, solutions, sprays, inhalants and/orpatches. Pharmaceutical compositions provided herein can be formulatedinto preparations in solid, semi-solid, or liquid forms suitable forlocal or topical administration, such as gels, water soluble jellies,creams, lotions, suspensions, foams, powders, slurries, ointments,solutions, oils, pastes, suppositories, sprays, emulsions, salinesolutions, dimethylsulfoxide (DMSO)-based solutions. In general,carriers with higher densities are capable of providing an area with aprolonged exposure to the active ingredients. In contrast, a solutionformulation can provide more immediate exposure of the active ingredientto the chosen area.

Generally, the active ingredient is admixed under sterile conditionswith a pharmaceutically acceptable carrier and/or any neededpreservatives and/or buffers as may be required. The pharmaceuticalcompositions also can comprise suitable solid or gel phase carriers orexcipients, which are compounds that allow increased penetration of, orassist in the delivery of, therapeutic molecules across the stratumcorneum permeability barrier of the skin. There are many of thesepenetration-enhancing molecules known to those trained in the art oftopical formulation. Examples of such carriers and excipients include,but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicacid), surfactants (e.g., isopropyl myristate and sodium laurylsulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes(e.g., menthol), amines, amides, alkanes, alkanols, water, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as polyethylene glycols.

Additionally, the use of transdermal patches, which often have the addedadvantage of providing controlled delivery of an active ingredient tothe body, is also contemplated herein. The construction and use oftransdermal patches for the delivery of pharmaceutical agents is wellknown in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and5,001,139. Such patches can be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents. Such dosage forms can beprepared, for example, by dissolving and/or dispensing the activeingredient in the proper medium. Alternatively or additionally, the ratecan be controlled by either providing a rate controlling membrane and/orby dispersing the active ingredient in a polymer matrix and/or gel.

Suitable devices for use in delivering intradermal pharmaceuticalcompositions described herein include short needle devices such as thosedescribed in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288;4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositionscan be administered by devices which limit the effective penetrationlength of a needle into the skin, such as those described in PCTpublication WO 99/34850 and functional equivalents thereof. Jetinjection devices which deliver liquid vaccines to the dermis via aliquid jet injector and/or via a needle which pierces the stratumcorneum and produces a jet which reaches the dermis are suitable. Jetinjection devices are described, for example, in U.S. Pat. Nos.5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratevaccine in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical mantoux method of intradermaladministration.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi liquid preparations such as liniments,lotions, oil in water and/or water in oil emulsions such as creams,ointments and/or pastes, and/or solutions and/or suspensions.Topically-administrable formulations can, for example, comprise fromabout 1% to about 10% (w/w) active ingredient, although theconcentration of the active ingredient can be as high as the solubilitylimit of the active ingredient in the solvent. In some embodiments,topically-administrable formulations can, for example, comprise fromabout 1% to about 9% (w/w) compound of formula (I), such as from about1% to about 8% (w/w), further such as from about 1% to about 7% (w/w),further such as from about 1% to about 6% (w/w), further such as fromabout 1% to about 5% (w/w), further such as from about 1% to about 4%(w/w), further such as from about 1% to about 3% (w/w), and further suchas from about 1% to about 2% (w/w) compound of formula (I). Formulationsfor topical administration can further comprise one or more of theadditional pharmaceutically acceptable excipients described herein.Formulations for topical administration can further comprise one or moreof the additional ingredients described herein.

A pharmaceutical composition provided herein can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration viathe buccal cavity. Pharmaceutical compositions for inhalation orinsufflation include solutions and suspensions in pharmaceuticallyacceptable, aqueous or organic solvents, or mixtures thereof, andpowders. The liquid or solid pharmaceutical compositions can containsuitable pharmaceutically acceptable excipients as described herein. Insome embodiments, the pharmaceutical compositions are administered bythe oral or nasal respiratory route for local or systemic effect.Pharmaceutical compositions in pharmaceutically acceptable solvents canbe nebulized by use of inert gases. Nebulized solutions can be inhaleddirectly from the nebulizing device or the nebulizing device can beattached to a face mask tent, or intermittent positive pressurebreathing machine. Solution, suspension, or powder pharmaceuticalcompositions can be administered, e.g., orally or nasally, from devicesthat deliver the formulation in an appropriate manner.

Such a formulation can comprise dry particles which comprise the activeingredient and which have a diameter in the range from about 0.5 toabout 7 nanometers or from about 1 to about 6 nanometers. Suchcompositions are conveniently in the form of dry powders foradministration using a device comprising a dry powder reservoir to whicha stream of propellant can be directed to disperse the powder and/orusing a self propelling solvent/powder dispensing container such as adevice comprising the active ingredient dissolved and/or suspended in alow-boiling propellant in a sealed container. Such powders compriseparticles wherein at least about 98% of the particles by weight have adiameter greater than about 0.5 nanometers and at least about 95% of theparticles by number have a diameter less than about 7 nanometers.Alternatively, at least about 95% of the particles by weight have adiameter greater than about 1 nanometer and at least about 90% of theparticles by number have a diameter less than about 6 nanometers. Drypowder compositions can include a solid fine powder diluent such assugar and are conveniently provided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below about 65° F. at atmospheric pressure. Generally,the propellant can constitute about 50 to about 99.9% (w/w) of thecomposition, and the active ingredient can constitute about 0.1 to about20% (w/w) of the composition. The propellant can further compriseadditional ingredients such as a liquid non-ionic and/or solid anionicsurfactant and/or a solid diluent (which can have a particle size of thesame order as particles comprising the active ingredient).

Pharmaceutical compositions formulated for pulmonary delivery canprovide the active ingredient in the form of droplets of a solutionand/or suspension. Such formulations can be prepared, packaged, and/orsold as aqueous and/or dilute alcoholic solutions and/or suspensions,optionally sterile, comprising the active ingredient, and canconveniently be administered using any nebulization and/or atomizationdevice. Such formulations can further comprise one or more additionalingredients including, but not limited to, a flavoring agent such assaccharin sodium, a volatile oil, a buffering agent, a surface activeagent, and/or a preservative such as methylhydroxybenzoate. The dropletsprovided by this route of administration can have an average diameter inthe range from about 0.1 to about 200 nanometers.

The formulations described herein as being useful for pulmonary deliveryare useful for intranasal delivery of a pharmaceutical composition.Another formulation suitable for intranasal administration is a coarsepowder comprising the active ingredient and having an average particlefrom about 0.2 to about 500 micrometers. Such a formulation isadministered in the manner in which snuff is taken, i.e. by rapidinhalation through the nasal passage from a container of the powder heldclose to the nares.

Formulations suitable for nasal administration can, for example,comprise from about as little as about 0.1% (w/w) and as much as about100% (w/w) of the active ingredient, and can comprise one or more of theadditional ingredients described herein. A pharmaceutical compositionprovided herein can be prepared, packaged, and/or sold in a formulationsuitable for buccal administration. Such formulations can, for example,be in the form of tablets and/or lozenges made using conventionalmethods, and can, for example, about 0.1 to about 20% (w/w) activeingredient, the balance comprising an orally dissolvable and/ordegradable composition and, optionally, one or more of the additionalingredients described herein. Alternately, formulations suitable forbuccal administration can comprise a powder and/or an aerosolized and/oratomized solution and/or suspension comprising the active ingredient.Such powdered, aerosolized, and/or aerosolized formulations, whendispersed, can have an average particle and/or droplet size in the rangefrom about 0.1 to about 200 nanometers, and can further comprise one ormore of the additional ingredients described herein.

A pharmaceutical composition provided herein can be prepared, packaged,and/or sold in a formulation suitable for ophthalmic administration.Such formulations can, for example, be in the form of eye dropsincluding, for example, an about 0.1/1.0% (w/w) solution and/orsuspension of the active ingredient in an aqueous or oily liquidcarrier. Such drops can further comprise buffering agents, salts, and/orone or more other of the additional ingredients described herein. Otheropthalmically-administrable formulations which are useful include thosewhich comprise the active ingredient in microcrystalline form and/or ina liposomal preparation. Ear drops and/or eye drops are alsocontemplated.

Pharmaceutical compositions suitable for ocular administration can bepresented as discrete dosage forms, such as drops or sprays eachcontaining a predetermined amount of an active ingredient a solution, ora suspension in an aqueous or non-aqueous liquid, an oil-in-wateremulsion, or a water-in-oil liquid emulsion. Other administration formsinclude, but are not limited to, intraocular injection, intravitrealinjection, topically, or through the use of a drug eluting device,microcapsule, implant, or microfluidic device. In some cases, thecompounds as disclosed herein are administered with a carrier orexcipient that increases the intraocular penetrance of the compound suchas an oil and water emulsion with colloid particles having an oily coresurrounded by an interfacial film. It is contemplated that all localroutes to the eye can be used, including topical, subconjunctival,periocular, retrobulbar, subtenon, intracameral, intravitreal,intraocular, subretinal, juxtascleral and suprachoroidal administration.Systemic or parenteral administration can be feasible including, but notlimited to, intravenous, subcutaneous, and oral delivery. An exemplarymethod of administration will be intravitreal or subtenon injection ofsolutions or suspensions, or intravitreal or subtenon placement ofbioerodible or non-bioerodible devices, or by topical ocularadministration of solutions or suspensions, or posterior juxtascleraladministration of a gel or cream formulation.

Eye drops can be prepared by dissolving the active ingredient in asterile aqueous solution such as physiological saline, bufferingsolution, etc., or by combining powder compositions to be dissolvedbefore use. Other vehicles can be chosen, as is known in the art,including, but not limited to: balance salt solution, saline solution,water soluble polyethers such as polyethyene glycol, polyvinyls, such aspolyvinyl alcohol and povidone, cellulose derivatives such asmethylcellulose and hydroxypropyl methylcellulose, petroleum derivativessuch as mineral oil and white petrolatum, animal fats such as lanolin,polymers of acrylic acid such as carboxypolymethylene gel, vegetablefats such as peanut oil and polysaccharides such as dextrans, andglycosaminoglycans such as sodium hyaluronate. In some embodiments,additives ordinarily used in the eye drops can be added. Such additivesinclude, but are not limited to, isotonizing agents (e.g., sodiumchloride, etc.), buffer agent (e.g., boric acid, sodium monohydrogenphosphate, sodium dihydrogen phosphate, etc.), preservatives (e.g.,benzalkonium chloride, benzethonium chloride, chlorobutanol, etc.),thickeners (e.g., saccharide such as lactose, mannitol, maltose, etc.;e.g., hyaluronic acid or its salt such as sodium hyaluronate, potassiumhyaluronate, etc.; e.g., mucopolysaccharide such as chondroitin sulfate,etc.; e.g., sodium polyacrylate, carboxyvinyl polymer, crosslinkedpolyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose,carboxymethyl cellulose, hydroxy propyl cellulose or other agents knownto those skilled in the art).

In some cases, the colloid particles include at least one cationic agentand at least one non-ionic surfactant such as a poloxamer, tyloxapol, apolysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester,or a polyoxyl stearate. In some cases, the cationic agent is analkylamine, a tertiary alkyl amine, a quaternary ammonium compound, acationic lipid, an amino alcohol, a biguanidine salt, a cationiccompound or a mixture thereof. In some cases, the cationic agent is abiguanidine salt such as chlorhexidine, polyaminopropyl biguanidine,phenformin, alkylbiguanidine, or a mixture thereof. In some cases, thequaternary ammonium compound is a benzalkonium halide, lauralkoniumhalide, cetrimide, hexadecyltrimethylammonium halide,tetradecyltrimethylammonium halide, dodecyltrimethylammonium halide,cetrimonium halide, benzethonium halide, behenalkonium halide,cetalkonium halide, cetethyldimonium halide, cetylpyridinium halide,benzododecinium halide, chlorallyl methenamine halide, rnyristylalkoniumhalide, stearalkonium halide or a mixture of two or more thereof. Insome cases, cationic agent is a benzalkonium chloride, lauralkoniumchloride, benzododecinium bromide, benzethenium chloride,hexadecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,dodecyltrimethylammonium bromide or a mixture of two or more thereof. Insome cases, the oil phase is mineral oil and light mineral oil, mediumchain triglycerides (MCT), coconut oil; hydrogenated oils comprisinghydrogenated cottonseed oil, hydrogenated palm oil, hydrogenate castoroil or hydrogenated soybean oil; polyoxyethylene hydrogenated castor oilderivatives comprising poluoxyl-40 hydrogenated castor oil, polyoxyl-60hydrogenated castor oil or polyoxyl-100 hydrogenated castor oil.

General considerations in the formulation and/or manufacture ofpharmaceutical agents can be found, for example, in Remington: TheScience and Practice of Pharmacy 21^(st) ed., Lippincott Williams &Wilkins, 2005.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with merely ordinary, if any,experimentation.

In some embodiments, provided herein are pharmaceutical compositions forcontrolled release administration containing a compound as disclosedherein, and a pharmaceutical excipient suitable for controlled releaseadministration. Active agents such as the compounds provided herein canbe administered by controlled release means or by delivery devices thatare well known to those of ordinary skill in the art. Examples include,but are not limited to, those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595;5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480;5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945;5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363;6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358;6,699,500 each of which is incorporated herein by reference. Such dosageforms can be used to provide slow or controlled release of one or moreactive agents using, for example, hydropropylmethyl cellulose, otherpolymer matrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the active agents provided herein. Thus, thepharmaceutical compositions provided encompass single unit dosage formssuitable for oral administration such as, but not limited to, tablets,capsules, gelcaps, and caplets that are adapted for controlled release.

All controlled release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non controlledcounterparts. In some embodiments, the use of a controlled releasepreparation in medical treatment is characterized by a minimum of drugsubstance being employed to cure or control the disease, disorder, orcondition in a minimum amount of time. Advantages of controlled releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased subject compliance. In addition, controlledrelease formulations can be used to affect the time of onset of actionor other characteristics, such as blood levels of the drug, and can thusaffect the occurrence of side (e.g., adverse) effects.

In some embodiments, controlled release formulations are designed toinitially release an amount of a compound as disclosed herein thatpromptly produces the desired therapeutic effect, and gradually andcontinually release other amounts of the compound to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In order to maintain this constant level of the compound in the body,the compound should be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled release of an active agent can be stimulated by variousconditions including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

In certain embodiments, the pharmaceutical composition can beadministered using intravenous infusion, an implantable osmotic pump, atransdermal patch, liposomes, or other modes of administration. In oneembodiment, a pump can be used (see, Sefton, CRC Crit. Ref Biomed. Eng.14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N.Engl. J. Med. 321:574 (1989)). In another embodiment, polymericmaterials can be used. In yet another embodiment, a controlled releasesystem can be placed in a subject at an appropriate site determined by apractitioner of skill, i.e., thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, Medical Applications of ControlledRelease, 115-138 (vol. 2, 1984). Other controlled release systems arediscussed in the review by Langer, Science 249:1527-1533 (1990). The oneor more active agents can be dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The one or more active agents then diffuse through the outer polymericmembrane in a release rate controlling step. The percentage of activeagent in such parenteral compositions is highly dependent on thespecific nature thereof, as well as the needs of the subject.

Kits

Also provided herein are kits comprising one or more compounds (orpharmaceutically acceptable forms thereof) provided herein, and/or apharmaceutical composition. Kits are typically provided in a suitablecontainer (e.g., for example, a foil, plastic, or cardboard package). Incertain embodiments, a kit can include one or more pharmaceuticalexcipients, pharmaceutical additives, therapeutically active agents, andthe like, as described herein. In certain embodiments, a kit can includemeans for proper administration, such as, for example, graduated cups,syringes, needles, cleaning aids, and the like. In certain embodiments,a kit can include instructions for proper administration and/orpreparation for proper administration.

The kits can include a compound or pharmaceutical composition asdescribed herein, in suitable packaging, and written material that caninclude instructions for use, discussion of clinical studies, listing ofside effects, and the like. Such kits can also include information, suchas scientific literature references, package insert materials, clinicaltrial results, and/or summaries of these and the like, which indicate orestablish the activities and/or advantages of the pharmaceuticalcomposition, and/or which describe dosing, administration, side effects,drug interactions, or other information useful to the health careprovider. Such information can be based on the results of variousstudies, for example, studies using experimental animals involving invivo models and studies based on human clinical trials.

In some embodiments, a memory aid is provided with the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several tablets or capsules to betaken on a given day.

The kit can further contain another agent. In some embodiments, thecompound as disclosed herein and the agent are provided as separatepharmaceutical compositions in separate containers within the kit. Insome embodiments, the compound as disclosed herein and the agent areprovided as a single pharmaceutical composition within a container inthe kit. Suitable packaging and additional articles for use (e.g.,measuring cup for liquid preparations, foil wrapping to minimizeexposure to air, and the like) are known in the art and can be includedin the kit. In other embodiments, kits can further comprise devices thatare used to administer the active agents. Examples of such devicesinclude, but are not limited to, syringes, drip bags, patches, andinhalers. Kits described herein can be provided, marketed and/orpromoted to health providers, including physicians, nurses, pharmacists,formulary officials, and the like. Kits can also, in some embodiments,be marketed directly to the consumer.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a transparent plastic material.During the packaging process, recesses are formed in the plastic foil.The recesses have the size and shape of the tablets or capsules to bepacked. Next, the tablets or capsules are placed in the recesses and thesheet of relatively stiff material is sealed against the plastic foil atthe face of the foil which is opposite from the direction in which therecesses were formed. As a result, the tablets or capsules are sealed inthe recesses between the plastic foil and the sheet. The strength of thesheet is such that the tablets or capsules can be removed from theblister pack by manually applying pressure on the recesses whereby anopening is formed in the sheet at the place of the recess. The tablet orcapsule can then be removed via said opening.

Kits can further comprise pharmaceutically acceptable vehicles that canbe used to administer one or more active agents. For example, if anactive agent is provided in a solid form that must be reconstituted forparenteral administration, the kit can comprise a sealed container of asuitable vehicle in which the active agent can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

5. Methods of Treatment

Provided herein are methods for treating, preventing and/or managing aMAGL-mediated condition comprising administering to a subject atherapeutically or prophylactically effective amount of a compoundprovided herein, or a pharmaceutically acceptable form (e.g., salts,prodrugs, tautomers, isomers, and/or isotopically labeled derivatives)thereof

Also provided herein are methods for inhibiting MAGL in a subjectcomprising administering to a subject a therapeutically effective amountof a compound provided herein or a pharmaceutically acceptable formthereof.

Also provided herein is a method of inhibiting activation of the MAGLpathway in vitro or ex vivo, comprising contacting a MAGL protein with acompound provided herein in an amount sufficient to reduce theactivation of the MAGL pathway.

Also provided herein is use of a compound provided herein for thetreatment of a MAGL-mediated condition in a subject.

Also provided herein is use of a compound provided herein in themanufacture of a medicament. In certain embodiments, the medicament isuseful for treating a MAGL-mediated condition.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or otherprimates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, includingcommercially relevant mammals such as cattle, pigs, horses, sheep,goats, cats, and/or dogs; and/or birds, including commercially relevantbirds such as chickens, ducks, geese, and/or turkeys.

As used herein “inhibition”, “inhibiting”, “inhibit” and “inhibitor”,and the like, refer to the ability of a compound to reduce, slow, haltor prevent activity of a particular biological process (e.g., MAGLactivity) in a cell relative to vehicle.

“MAGL-mediated condition” as used herein, refers to a disease, disorderor condition which is treatable by inhibition of MAGL activity.“Disease”, “disorder” or “condition” are terms used interchangeablyherein. MAGL-mediated conditions include, but are not limited to,painful conditions, inflammatory conditions, immune disorders, disordersof the central nervous system, metabolic disorders, cardiac disordersand glaucoma.

In certain embodiments, the MAGL-mediated condition is a painfulcondition. As used herein, a “painful condition” includes, but is notlimited to, neuropathic pain (e.g., peripheral neuropathic pain),central pain, deafferentiation pain, chronic pain (e.g., chronicnociceptive pain, and other forms of chronic pain such as post-operativepain, e.g., pain arising after hip, knee, or other replacement surgery),pre-operative pain, stimulus of nociceptive receptors (nociceptivepain), acute pain (e.g., phantom and transient acute pain),non-inflammatory pain, inflammatory pain, pain associated with cancer,wound pain, burn pain, post-operative pain, pain associated with medicalprocedures, pain resulting from pruritus, painful bladder syndrome, painassociated with premenstrual dysphoric disorder and/or premenstrualsyndrome, pain associated with chronic fatigue syndrome, pain associatedwith pre-term labor, pain associated with withdrawl symptoms from drugaddiction, joint pain, arthritic pain (e.g., pain associated withcrystalline arthritis, osteoarthritis, psoriatic arthritis, goutyarthritis, reactive arthritis, rheumatoid arthritis or Reiter'sarthritis), lumbosacral pain, musculo-skeletal pain, headache, migraine,muscle ache, lower back pain, neck pain, toothache, dental/maxillofacialpain, visceral pain and the like.

One or more of the painful conditions contemplated herein can comprisemixtures of various types of pain provided above and herein (e.g.nociceptive pain, inflammatory pain, neuropathic pain, etc.). In someembodiments, a particular pain can dominate. In other embodiments, thepainful condition comprises two or more types of pains without onedominating. A skilled clinician can determine the dosage to achieve atherapeutically effective amount for a particular subject based on thepainful condition.

In certain embodiments, the painful condition is neuropathic pain. Theterm “neuropathic pain” refers to pain resulting from injury to a nerve.Neuropathic pain is distinguished from nociceptive pain, which is thepain caused by acute tissue injury involving small cutaneous nerves orsmall nerves in muscle or connective tissue. Neuropathic pain typicallyis long-lasting or chronic and often develops days or months followingan initial acute tissue injury. Neuropathic pain can involve persistent,spontaneous pain as well as allodynia, which is a painful response to astimulus that normally is not painful. Neuropathic pain also can becharacterized by hyperalgesia, in which there is an accentuated responseto a painful stimulus that usually is trivial, such as a pin prick.Neuropathic pain conditions can develop following neuronal injury andthe resulting pain can persist for months or years, even after theoriginal injury has healed. Neuronal injury can occur in the peripheralnerves, dorsal roots, spinal cord or certain regions in the brain.Neuropathic pain conditions include, but are not limited to, diabeticneuropathy (e.g., peripheral diabetic neuropathy); sciatica;non-specific lower back pain; multiple sclerosis pain; carpal tunnelsyndrome, fibromyalgia; HIV-related neuropathy; neuralgia (e.g.,post-herpetic neuralgia, trigeminal neuralgia); pain resulting fromphysical trauma (e.g., amputation; surgery, invasive medical procedures,toxins, burns, infection), pain resulting from cancer or chemotherapy(e.g., chemotherapy-induced pain such as chemotherapy-induced peripheralneuropathy), and pain resulting from an inflammatory condition (e.g., achronic inflammatory condition). Neuropathic pain can result from aperipheral nerve disorder such as neuroma; nerve compression; nervecrush, nerve stretch or incomplete nerve transsection; mononeuropathy orpolyneuropathy. Neuropathic pain can also result from a disorder such asdorsal root ganglion compression; inflammation of the spinal cord;contusion, tumor or hemisection of the spinal cord; tumors of thebrainstem, thalamus or cortex; or trauma to the brainstem, thalamus orcortex.

The symptoms of neuropathic pain are heterogeneous and are oftendescribed as spontaneous shooting and lancinating pain, or ongoing,burning pain. In addition, there is pain associated with normallynon-painful sensations such as “pins and needles” (paraesthesias anddysesthesias), increased sensitivity to touch (hyperesthesia), painfulsensation following innocuous stimulation (dynamic, static or thermalallodynia), increased sensitivity to noxious stimuli (thermal, cold,mechanical hyperalgesia), continuing pain sensation after removal of thestimulation (hyperpathia) or an absence of or deficit in selectivesensory pathways (hypoalgesia).

In certain embodiments, the painful condition is non-inflammatory pain.The types of non-inflammatory pain include, without limitation,peripheral neuropathic pain (e.g., pain caused by a lesion ordysfunction in the peripheral nervous system), central pain (e.g., paincaused by a lesion or dysfunction of the central nervous system),deafferentation pain (e.g., pain due to loss of sensory input to thecentral nervous system), chronic nociceptive pain (e.g., certain typesof cancer pain), noxious stimulus of nociceptive receptors (e.g., painfelt in response to tissue damage or impending tissue damage), phantompain (e.g., pain felt in a part of the body that no longer exists, suchas a limb that has been amputated), pain felt by psychiatric subjects(e.g., pain where no physical cause may exist), and wandering pain(e.g., wherein the pain repeatedly changes location in the body).

In certain embodiments, the painful condition is inflammatory pain. Incertain embodiments, the painful condition (e.g., inflammatory pain) isassociated with an inflammatory condition and/or an immune disorder.

In certain embodiments, the MAGL-mediated condition is an inflammatorycondition. The term “inflammatory condition” refers to those diseases,disorders or conditions that are characterized by signs of pain (dolor,from the generation of noxious substances and the stimulation ofnerves), heat (calor, from vasodilatation), redness (rubor, fromvasodilatation and increased blood flow), swelling (tumor, fromexcessive inflow or restricted outflow of fluid), and/or loss offunction (functio laesa, which can be partial or complete, temporary orpermanent. Inflammation takes on many forms and includes, but is notlimited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic,diffuse, disseminated, exudative, fibrinous, fibrosing, focal,granulomatous, hyperplastic, hypertrophic, interstitial, metastatic,necrotic, obliterative, parenchymatous, plastic, productive,proliferous, pseudomembranous, purulent, sclerosing, seroplastic,serous, simple, specific, subacute, suppurative, toxic, traumatic,and/or ulcerative inflammation.

Exemplary inflammatory conditions include, but are not limited to,inflammation associated with acne, anemia (e.g., aplastic anemia,haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis,temporal arteritis, periarteritis nodosa, Takayasu's arteritis),arthritis (e.g., crystalline arthritis, osteoarthritis, psoriaticarthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis andReiter's arthritis), ankylosing spondylitis, amylosis, amyotrophiclateral sclerosis, autoimmune diseases, allergies or allergic reactions,atherosclerosis, bronchitis, bursitis, chronic prostatitis,conjunctivitis, Chagas disease, chronic obstructive pulmonary disease,cermatomyositis, diverticulitis, diabetes (e.g., type I diabetesmellitus, type 2 diabetes mellitus), a skin condition (e.g., psoriasis,eczema, burns, dermatitis, pruritus (itch)), endometriosis,Guillain-Barre syndrome, infection, ischaemic heart disease, Kawasakidisease, glomerulonephritis, gingivitis, hypersensitivity, headaches(e.g., migraine headaches, tension headaches), ileus (e.g.,postoperative ileus and ileus during sepsis), idiopathicthrombocytopenic purpura, interstitial cystitis (a.k.a., “painfulbladder syndrome”), gastrointestinal disorder (e.g., selected frompeptic ulcers, regional enteritis, diverticulitis, gastrointestinalbleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilicesophagitis, eosinophilic gastritis, eosinophilic gastroenteritis,eosinophilic colitis), gastritis, diarrhea, gastroesophageal refluxdisease (GORD, or its synonym GERD), inflammatory bowel disease (IBD)(e.g., Crohn's disease, ulcerative colitis, collagenous colitis,lymphocytic colitis, ischaemic colitis, diversion colitis, Behcet'ssyndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)),lupus, multiple sclerosis, morphea, myeasthenia gravis, myocardialischemia, nephrotic syndrome, pemphigus vulgaris, pernicious aneaemia,peptic ulcers, polymyositis, primary biliary cirrhosis,neuroinflammation associated with brain disorders (e.g., Parkinson'sdisease, Huntington's disease, and Alzheimer's disease), prostatitis,chronic inflammation associated with cranial radiation injury, pelvicinflammatory disease, reperfusion injury, regional enteritis, rheumaticfever, systemic lupus erythematosus, schleroderma, scierodoma,sarcoidosis, spondyloarthopathies, Sjogren's syndrome, thyroiditis,transplantation rejection, tendonitis, trauma or injury (e.g.,frostbite, chemical irritants, toxins, scarring, burns, physicalinjury), vasculitis, vitiligo and Wegener's granulomatosis. In certainembodiments, the inflammatory disorder is selected from arthritis (e.g.,rheumatoid arthritis), inflammatory bowel disease, inflammatory bowelsyndrome, asthma, psoriasis, endometriosis, interstitial cystitis andprostatistis. In certain embodiments, the inflammatory condition is anacute inflammatory condition (e.g., for example, inflammation resultingfrom infection). In certain embodiments, the inflammatory condition is achronic inflammatory condition (e.g., conditions resulting from asthma,arthritis and inflammatory bowel disease). The compounds can also beuseful in treating inflammation associated with trauma andnon-inflammatory myalgia. The compounds can also be useful in treatinginflammation associated with cancer.

In certain embodiments, the MAGL-mediated condition is an immunedisorder. Immune disorders, such as auto-immune disorders, include, butare not limited to, arthritis (including rheumatoid arthritis,spondyloarthopathies, gouty arthritis, degenerative joint diseases suchas osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome,ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease,haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateralsclerosis, amylosis, acute painful shoulder, psoriatic, and juvenilearthritis), asthma, atherosclerosis, osteoporosis, bronchitis,tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, burns,dermatitis, pruritus (itch)), enuresis, eosinophilic disease,gastrointestinal disorder (e.g., selected from peptic ulcers, regionalenteritis, diverticulitis, gastrointestinal bleeding, eosinophilicgastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilicgastritis, eosinophilic gastroenteritis, eosinophilic colitis),gastritis, diarrhea, gastroesophageal reflux disease (GORD, or itssynonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease,ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemiccolitis, diversion colitis, Behcet's syndrome, indeterminate colitis)and inflammatory bowel syndrome (IBS)), and disorders ameliorated by agastroprokinetic agent (e.g., ileus, postoperative ileus and ileusduring sepsis; gastroesophageal reflux disease (GORD, or its synonymGERD); eosinophilic esophagitis, gastroparesis such as diabeticgastroparesis; food intolerances and food allergies and other functionalbowel disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiacchest pain (NCCP, including costo-chondritis)).

In certain embodiments, the inflammatory disorder and/or the immunedisorder is a gastrointestinal disorder. In some embodiments, thegastrointestinal disorder is selected from gastrointestinal disorder(e.g., selected from peptic ulcers, regional enteritis, diverticulitis,gastrointestinal bleeding, eosinophilic gastrointestinal disorders(e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilicgastroenteritis, eosinophilic colitis), gastritis, diarrhea,gastroesophageal reflux disease (GORD, or its synonym GERD),inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerativecolitis, collagenous colitis, lymphocytic colitis, ischaemic colitis,diversion colitis, Behcet's syndrome, indeterminate colitis) andinflammatory bowel syndrome (IBS)). In certain embodiments, thegastrointestinal disorder is inflammatory bowel disease (IBD).

In certain embodiments, the inflammatory condition and/or immunedisorder is a skin condition. In some embodiments, the skin condition ispruritus (itch), psoriasis, eczema, burns or dermatitis. In certainembodiments, the skin condition is psoriasis. In certain embodiments,the skin condition is pruritis.

In certain embodiments, the MAGL-mediated condition is a disorder of thecentral nervous system (CNS) (“CNS disorder”). Exemplary CNS disordersinclude, but are not limited to, neurotoxicity and/or neurotrauma,stroke, multiple sclerosis, spinal cord injury, epilepsy, a mentaldisorder, a sleep condition, a movement disorder, nausea and/or emesis,amyotrophic lateral sclerosis, Alzheimer's disease and addiction (e.g.,drug addiction).

In certain embodiments, the CNS disorder is neurotoxicity and/orneurotrauma, e.g., for example, as a result of acute neuronal injury(e.g., tramatic brain injury (TBI), stroke, epilepsy) or a chronicneurodegenerative disorder (e.g., multiple sclerosis, Parkinson'sdisease, Huntington's disease, amyotrophic lateral sclerosis,Alzheimer's disease). In certain embodiments, the compound of providedherein are a neuroprotective effect, e.g., against an acute neuronalinjury or a chronic neurodegenerative disorder.

In certain embodiments, the CNS disorder is stroke (e.g., ischemicstroke).

In certain embodiments, the CNS disorder is multiple sclerosis.

In certain embodiments, the CNS disorder is spinal cord injury.

In certain embodiments, the CNS disorder is epilepsy.

In certain embodiments, the CNS disorder is a mental disorder, e.g., forexample, depression, anxiety or anxiety-related conditions, a learningdisability or schizophrenia.

In certain embodiments, the CNS disorder is depression. “Depression,” asused herein, includes, but is not limited to, depressive disorders orconditions, such as, for example, major depressive disorders (e.g.,unipolar depression), dysthymic disorders (e.g., chronic, milddepression), bipolar disorders (e.g., manic-depression), seasonalaffective disorder, and/or depression associated with drug addiction(e.g., withdrawal). The depression can be clinical or subclinicaldepression. The depression can be associated with or prementrualsyndrome and/or premenstrual dysphoric disorder.

In certain embodiments, the CNS disorder is anxiety. “Anxiety,” as usedherein, includes, but is not limited to anxiety and anxiety-relatedconditions, such as, for example, clinical anxiety, panic disorder,agoraphobia, generalized anxiety disorder, specific phobia, socialphobia, obsessive-compulsive disorder, acute stress disorder,post-traumatic stress disorder, adjustment disorders with anxiousfeatures, anxiety disorder associated with depression, anxiety disorderdue to general medical conditions, and substance-induced anxietydisorders, anxiety associated with drug addiction (e.g., withdrawal,dependence, reinstatement) and anxiety associated with nausea and/oremesis. This treatment can also be to induce or promote sleep in asubject (e.g., for example, a subject with anxiety).

In certain embodiments, the CNS disorder is a learning disorder (e.g.,attention deficit disorder (ADD)).

In certain embodiments, the CNS disorder is schizophrenia.

In certain embodiments, the CNS disorder is a sleep condition. “Sleepconditions” include, but are not limited to, insomia, narcolepsy, sleepapnea, restless legs syndrome (RLS), delayed sleep phase syndrome(DSPS), periodic limb movement disorder (PLMD), hypopnea syndrome, rapideye movement behavior disorder (RBD), shift work sleep condition (SWSD),and sleep problems (e.g., parasomnias) such as nightmares, nightterrors, sleep talking, head banging, snoring, and clenched jaw and/orgrinding of teeth (bruxism).

In certain embodiments, the CNS disorder is a movement disorder, e.g.,basal ganglia disorders, such as, for example, Parkinson's disease,levodopa-induced dyskinesia, Huntington's disease, Gilles de laTourette's syndrome, tardive diskinesia and dystonia. Other movementdisorders include, but are not limited to, ataxia, tremor, essentialtremor, myclonus and startle, movement tics, restless legs syndrome,Stiff person syndrome and Gait disorders.

In certain embodiments, the CNS disorder is Alzheimer's disease.

In certain embodiments, the CNS disorder is amyotrophic lateralsclerosis (ALS).

In certain embodiments, the CNS disorder is nausea and/or emesis.

In certain embodiments, the CNS disorder is addiction (e.g., forinstance, drug addiction, e.g., addiction to opiates, nicotine, cocaine,psychostimulants and/or alcohol).

In still yet other embodiments, the MAGL-mediated condition is a cardiacdisorder, e.g., for example, selected from hypertension, circulatoryshock, myocardial reperfusion injury and atherosclerosis.

In certain embodiments, the MAGL-mediated condition is a metabolicdisorder (e.g., a wasting condition, an obesity-related condition orcomplication thereof).

In certain embodiments, the metabolic disorder is a wasting condition. A“wasting condition,” as used herein, includes, but is not limited to,anorexia and cachexias of various natures (e.g., weight loss associatedwith cancer, weight loss associated with other general medicalconditions, weight loss associated with failure to thrive, and thelike).

In certain embodiments, the metabolic disorder is an obesity-relatedcondition or a complication thereof. An “obesity-related condition” asused herein, includes, but is not limited to, obesity, undesired weightgain (e.g., from medication-induced weight gain, from cessation ofsmoking) and an over-eating disorder (e.g., binge eating, bulimia,compulsive eating, or a lack of appetite control each of which canoptionally lead to undesired weight gain or obesity). “Obesity” and“obese” as used herein, refers to class I obesity, class II obesity,class III obesity and pre-obesity (e.g., being “over-weight”) as definedby the World Health Organization.

Reduction of storage fat is expected to provide various primary and/orsecondary benefits in a subject (e.g., in a subject diagnosed with acomplication associated with obesity) such as, for example, an increasedinsulin responsiveness (e.g., in a subject diagnosed with Type IIdiabetes mellitus); a reduction in elevated blood pressure; a reductionin elevated cholesterol levels; and/or a reduction (or a reduced risk orprogression) of ischemic heart disease, arterial vascular disease,angina, myocardial infarction, stroke, migraines, congestive heartfailure, deep vein thrombosis, pulmonary embolism, gall stones,gastroesophagael reflux disease, obstructive sleep apnea, obesityhypoventilation syndrome, asthma, gout, poor mobility, back pain,erectile dysfunction, urinary incontinence, liver injury (e.g., fattyliver disease, liver cirrhosis, alcoholic cirrhosis, endotoxin mediatedliver injury) or chronic renal failure. Thus, the method provided hereinis applicable to obese subjects, diabetic subjects, and alcoholicsubjects.

In some embodiments, treatment of an obesity-related condition orcomplication thereof involves reduction of body weight in the subject.In some embodiments, treatment of an obesity-related condition orcomplication thereof involves appetite control in the subject.

In other embodiments, the MAGL-mediated condition is glaucoma.

In certain embodiments, the MAGL-mediated condition is cancer. As usedherein, “cancer” encompasses all types and manifestations of cancer.Exemplary cancers include, but are not limited to, breast cancer such asa ductal carcinoma in duct tissue in a mammary gland, medullarycarcinomas, colloid carcinomas, tubular carcinomas, and inflammatorybreast cancer; ovarian cancer, including epithelial ovarian tumors suchas adenocarcinoma in the ovary and an adenocarcinoma that has migratedfrom the ovary into the abdominal cavity; uterine cancer; cervicalcancer such as adenocarcinoma in the cervix epithelial includingsquamous cell carcinoma and adenocarcinomas; prostate cancer, such as aprostate cancer selected from the following: an adenocarcinoma or anadenocarinoma that has migrated to the bone; pancreatic cancer such asepitheliod carcinoma in the pancreatic duct tissue and an adenocarcinomain a pancreatic duct; bladder cancer such as a transitional cellcarcinoma in urinary bladder, urothelial carcinomas (transitional cellcarcinomas), tumors in the urothelial cells that line the bladder,squamous cell carcinomas, adenocarcinomas, and small cell cancers;leukemia such as acute myeloid leukemia (AML), acute lymphocyticleukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairycell leukemia, myelodysplasia, myeloproliferative disorders, NK cellleukemia (e.g., blastic plasmacytoid dendritic cell neoplasm), acutemyelogenous leukemia (AML), chronic myelogenous leukemia (CML),mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM),and myelodysplastic syndrome (MDS); bone cancer; lung cancer such asnon-small cell lung cancer (NSCLC), which is divided into squamous cellcarcinomas, adenocarcinomas, and large cell undifferentiated carcinomas,and small cell lung cancer; skin cancer such as basal cell carcinoma,melanoma, squamous cell carcinoma and actinic keratosis, which is a skincondition that sometimes develops into squamous cell carcinoma; eyeretinoblastoma; cutaneous or intraocular (eye) melanoma; primary livercancer (cancer that begins in the liver); kidney cancer; thyroid cancersuch as papillary, follicular, medullary and anaplastic; lymphoma suchas diffuse large B-cell lymphoma, B-cell immunoblastic lymphoma, NK celllymphoma (e.g., blastic plasmacytoid dendritic cell neoplasm), and smallnon-cleaved cell lymphoma; Kaposi's Sarcoma; viral-induced cancersincluding hepatitis B virus (HBV), hepatitis C virus (HCV), andhepatocellular carcinoma; human lymphotropic virus-type 1 (HTLV-1) andadult T-cell leukemia/lymphoma; and human papilloma virus (HPV) andcervical cancer; central nervous system cancers (CNS) such as primarybrain tumor, which includes gliomas (astrocytoma, anaplasticastrocytoma, or glioblastoma multiforme), Oligodendroglioma, Ependymoma,Meningioma, Lymphoma, Schwannoma, and Medulloblastoma; peripheralnervous system (PNS) cancers such as acoustic neuromas and malignantperipheral nerve sheath tumor (MPNST) including neurofibromas andschwannomas, malignant fibrous cytoma, malignant fibrous histiocytoma,malignant meningioma, malignant mesothelioma, and malignant mixedMüllerian tumor; oral cavity and oropharyngeal cancer such as,hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, andoropharyngeal cancer; stomach cancer such as lymphomas, gastric stromaltumors, and carcinoid tumors; testicular cancer such as germ cell tumors(GCTs), which include seminomas and nonseminomas, and gonadal stromaltumors, which include Leydig cell tumors and Sertoli cell tumors; thymuscancer such as to thymomas, thymic carcinomas, Hodgkin disease,non-Hodgkin lymphomas carcinoids or carcinoid tumors; rectal cancer; andcolon cancer. In one embodiment, the cancer is melanoma. In anotherembodiment, the cancer is ovarian cancer. In yet another embodiment, thecancer is breast cancer.

In one embodiment, the cancer is a hematological cancer. Exemplaryhematological cancers include, but are not limited to, acute myeloidleukemia (AML), multiple myeloma (MM), and chronic lymphocytic leukemia(CLL).

In one embodiment, the cancer is a solid tumor (e.g., gliomas).

In one embodiment, provided herein are methods for treating, preventingand/or managing a cancer comprising administering to a subject atherapeutically or prophylactically effective amount of a compoundprovided herein, or a pharmaceutically acceptable form (e.g., salts,prodrugs, tautomers, isomers, and/or isotopically labeled derivatives)thereof

In one embodiment, provided herein are methods for suppressing theaggressiveness (e.g., migration, invasion, and survival) of a cancercell comprising administering to a subject a therapeutically orprophylactically effective amount of a compound provided herein, or apharmaceutically acceptable form (e.g., salts, prodrugs, tautomers,isomers, and/or isotopically labeled derivatives) thereof

6. Administration

The compounds can be administered using any amount and any route ofadministration effective for treatment. The exact amount required willvary from subject to subject, depending on the species, age, and generalcondition of the subject, the severity of the infection, the particularcomposition, its mode of administration, its mode of activity, and thelike. The compounds provided herein are typically formulated in dosageunit form for ease of administration and uniformity of dosage. It willbe understood, however, that the total daily usage of the compositionswill be decided by the attending physician within the scope of soundmedical judgment. The specific therapeutically effective dose level forany particular subject or organism will depend upon a variety of factorsincluding, but not limited to, the disease, disorder, or condition beingtreated and the severity of the disorder; the activity of the specificactive ingredient employed; the specific composition employed; the age,body weight, general health, sex and diet of the subject; the time ofadministration, route of administration, and rate of excretion of thespecific active ingredient employed; the duration of the treatment;drugs used in combination or coincidental with the specific activeingredient employed; and like factors well known in the medical arts.

The compounds and compositions provided herein can be administered byany route. In some embodiments, the compounds and compositions areadministered via a variety of routes, including, but not limited to,oral, intravenous, intramuscular, intra-arterial, intramedullary,intrathecal, subcutaneous, intraventricular, transdermal, interdermal,rectal, intravaginal, intraperitoneal, topical (as by powders,ointments, creams, and/or drops), mucosal, nasal, bucal, enteral,sublingual; by intratracheal instillation, bronchial instillation,and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.Specifically contemplated routes are systemic intravenous injection,regional administration via blood and/or lymph supply, and/or directadministration to an affected site. In general the most appropriateroute of administration will depend upon a variety of factors includingthe nature of the agent (e.g., its stability in the environment of thegastrointestinal tract), the condition of the subject (e.g., whether thesubject is able to tolerate oral administration), etc. At present theoral and/or nasal spray and/or aerosol route is most commonly used todeliver therapeutic agents directly to the lungs and/or respiratorysystem. However, the delivery of the pharmaceutical composition by anyappropriate route taking into consideration likely advances in thesciences of drug delivery is also encompassed herein.

The exact amount of a compound required to achieve a therapeuticallyeffective amount will vary from subject to subject, depending onspecies, age, and general condition of a subject, severity of the sideeffects or disorder, identity of the particular compound(s), mode ofadministration, and the like. A given dosage can be delivered threetimes a day, two times a day, once a day, every other day, every thirdday, every week, every two weeks, every three weeks, or every fourweeks. In certain embodiments, the given dosage can be delivered usingmultiple administrations (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or moreadministrations).

In certain embodiments, a therapeutically effective amount of a compoundprovided herein for administration one or more times a day to a 70 kgadult human can comprise about 0.0001 mg to about 1000 mg of a compoundper unit dosage form. It will be appreciated that dose ranges asdescribed herein provide guidance for the administration ofpharmaceutical compositions to an adult. The amount to be administeredto, for example, a child or an adolescent can be determined by a medicalpractitioner or person skilled in the art and can be lower or the sameas that administered to an adult.

It will be also appreciated that a compound or composition, as describedabove and herein, can be administered in combination with one or moreadditional therapeutically active agents.

By “in combination with,” it is not intended to imply that the agentsmust be administered at the same time and/or formulated for deliverytogether, although these methods of delivery are certainly within thescope. The compositions can be administered concurrently with, prior to,or subsequent to, one or more other additional therapeutically activeagents. In general, each agent will be administered at a dose and/or ona time schedule determined for that agent. In will further beappreciated that the additional therapeutically active agent utilized inthis combination can be administered together in a single composition oradministered separately in different compositions. The particularcombination to employ in a regimen will take into account compatibilityof the compound with the additional therapeutically active agent and/orthe desired therapeutic effect to be achieved. In some embodiments,administration of two or more agents to subject occurs so that bothagents and/or their metabolites are present in the subject at the sametime.

In some embodiments, additional therapeutically active agents utilizedin combination be utilized at levels that do not exceed the levels atwhich they are utilized individually. In some embodiments, the levelsutilized in combination will be lower than those utilized individually.

By a “therapeutically active agent” or “active agent” refers to anysubstance that is useful for therapy, including prophylactic andtherapeutic treatment.

Also provided is the delivery of the pharmaceutical compositions incombination with agents that can improve their bioavailability, reduceand/or modify their metabolism, inhibit their excretion, and/or modifytheir distribution within the body. It will also be appreciated that thetherapy employed can achieve a desired effect for the same disorder (forexample, a compound can be administered in combination with ananti-inflammatory, anti-anxiety and/or anti-depressive agent, etc.),and/or they can achieve different effects (e.g., control of any adverseside-effects).

Exemplary active agents include, but are not limited to, anti-canceragents, antibiotics, anti-viral agents, anesthetics, anti-coagulants,inhibitors of an enzyme, steroidal agents, steroidal or non-steroidalanti-inflammatory agents, antihistamine, immunosuppressant agents,antineoplastic agents, antigens, vaccines, antibodies, decongestant,ssedatives, opioids, pain-relieving agents, analgesics, anti-pyretics,hormones, prostaglandins, progestational agents, anti-glaucoma agents,ophthalmic agents, anti-cholinergics, anti-depressants, anti-psychotics,hypnotics, tranquilizers, anti-convulsants, muscle relaxants,anti-spasmodics, muscle contractants, channel blockers, miotic agents,anti-secretory agents, anti-thrombotic agents, anticoagulants,anti-cholinergics, β-adrenergic blocking agents, diuretics,cardiovascular active agents, vasoactive agents, vasodilating agents,anti-hypertensive agents, angiogenic agents, modulators ofcellextracellular matrix interactions (e.g. cell growth inhibitors andanti-adhesion molecules), or inhibitors/intercalators of DNA, RNA,protein-protein interactions, protein-receptor interactions, etc. Activeagents include, but are not limited to, small organic molecules such asdrug compounds (e.g., compounds approved by the Food and DrugsAdministration as provided in the Code of Federal Regulations (CFR)),peptides, proteins, carbohydrates, monosaccharides, oligosaccharides,polysaccharides, nucleoproteins, mucoproteins, lipoproteins, syntheticpolypeptides or proteins, small molecules linked to proteins,glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides,nucleosides, oligonucleotides, antisense oligonucleotides, lipids,hormones, vitamins and cells.

In certain embodiments, the additional therapeutically active agent is apain-relieving agent. In other embodiments, the additionaltherapeutically active agent is an anti-inflammatory agent.

In another aspect, provided herein is a pharmaceutical composition forinhibiting abnormal cell growth in a subject which comprises an amountof a compound as provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, in combinationwith an amount of an anti-cancer agent (e.g., a chemotherapeutic agent).Many chemotherapeutics are presently known in the art and can be used incombination with the compounds as provided herein.

In some embodiments, the chemotherapeutic is selected from mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, and anti-androgens. Non-limiting examples arechemotherapeutic agents, cytotoxic agents, and non-peptide smallmolecules such as Gleevec® (Imatinib Mesylate), Velcade® (bortezomib),Casodex (bicalutamide), Iressa®, and Adriamycin as well as a host ofchemotherapeutic agents. Non-limiting examples of chemotherapeuticagents include alkylating agents such as thiotepa and cyclosphosphamide(CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan andpiposulfan; aziridines such as benzodopa, carboquone, meturedopa, anduredopa; ethylenimines and methylamelamines including altretamine,triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; BTK inhibitorssuch as ibrutinib (PCI-32765) and AVL-292; HDAC inhibitors such asvorinostat, romidepsin, panobinostat, valproic acid, belinostat,mocetinostat, abrexinostat, entinostat, SB939, resminostat, givinostat,CUDC-101, AR-42, CHR-2845, CHR-3996, 4SC-202, CG200745, ACY-1215 andkevetrin; JAK/STAT inhibitors such as lestaurtinib, tofacitinib,ruxolitinib, pacritinib, CYT387, baricitinib, fostamatinib, GLPG0636,TG101348, INCB16562 and AZD1480; nitrogen mustards such as bedamustine,chlorambucil, chlornaphazine, cholophosphamide, estramustine,ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride,melphalan, novembichin, phenesterine, prednimustine, trofosfamide,uracil mustard; nitrosureas such as carmustine, chlorozotocin,fotemustine, lomustine, nimustine, ranimustine; antibiotics such asaclacinomysins, actinomycin, authramycin, azaserine, bleomycins,cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin,Casodex™, chromomycins, dactinomycin, daunorubicin, detorubicin,6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin,idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin,olivomycins, peplomycin, potfiromycin, puromycin, quelamycin,rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex,zinostatin, zorubicin; anti-metabolites such as methotrexate and5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pralatrexate, pteropterin, trimetrexate; purine analogssuch as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine,carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine,floxuridine, androgens such as calusterone, dromostanolone propionate,epitiostanol, mepitiostane, testolactone; anti-adrenals such asaminoglutethimide, mitotane, trilostane; folic acid replenisher such asfrolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinicacid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine;demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone;mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane;sizofiran; spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethyla-mine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.,paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France) and ABRAXANE®(paclitaxel protein-bound particles); retinoic acid; esperamicins;capecitabine; and pharmaceutically acceptable forms (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) of any of the above.Also included as suitable chemotherapeutic cell conditioners areanti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens including for example tamoxifen(Nolvadex™), raloxifene, aromatase inhibiting 4(5)-imidazoles,4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, andtoremifene (Fareston); and anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine;6-thioguanine; mercaptopurine; methotrexate; platinum analogs such ascisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16);ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine;navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda;ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO). Where desired, the compounds orpharmaceutical composition as provided herein can be used in combinationwith commonly prescribed anti-cancer drugs such as Herceptin®, Avastin,Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere, ABVD, AVICINE,Abagovomab, Acridine carboxamide, Adecatumumab,17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib,3-Aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide,Anthracenedione, Anti-CD22 immunotoxins, Antineoplastic, Antitumorigenicherbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine,BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximine,CBV (chemotherapy), Calyculin, Crizotinib, cell-cycle nonspecificantineoplastic agents, Dichloroacetic acid, Discodermolide,Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan,Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE chemotherapy regimen,IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, Laniquidar,Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide,Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1,Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin, Resiquimod,Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford V,Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel,Triplatin tetranitrate, Tris(2-chloroethyl)amine, Troxacitabine,Uramustine, Vadimezan, Vinflunine, ZD6126, and Zosuquidar.

In some embodiments, the chemotherapeutic is selected from hedgehoginhibitors including, but not limited to IPI-926 (See U.S. Pat. No.7,812,164). Other suitable hedgehog inhibitors include, for example,those described and provided in U.S. Pat. No. 7,230,004, U.S. PatentApplication Publication No. 2008/0293754, U.S. Patent ApplicationPublication No. 2008/0287420, and U.S. Patent Application PublicationNo. 2008/0293755, the entire disclosures of which are incorporated byreference herein. Examples of other suitable hedgehog inhibitors includethose described in U.S. Patent Application Publication Nos. US2002/0006931, US 2007/0021493 and US 2007/0060546, and InternationalApplication Publication Nos. WO 2001/19800, WO 2001/26644, WO2001/27135, WO 2001/49279, WO 2001/74344, WO 2003/011219, WO2003/088970, WO 2004/020599, WO 2005/013800, WO 2005/033288, WO2005/032343, WO 2005/042700, WO 2006/028958, WO 2006/050351, WO2006/078283, WO 2007/054623, WO 2007/059157, WO 2007/120827, WO2007/131201, WO 2008/070357, WO 2008/110611, WO 2008/112913, and WO2008/131354. Additional examples of hedgehog inhibitors include, but arenot limited to, GDC-0449 (also known as RG3616 or vismodegib) describedin, e.g., Von Hoff D. et al., N. Engl. J. Med. 2009; 361(12):1164-72;Robarge K. D. et al., Bioorg Med Chem Lett. 2009; 19(19):5576-81; Yauch,R. L. et al. (2009) Science 326: 572-574; Sciencexpress: 1-3(10.1126/science.1179386); Rudin, C. et al. (2009) New England J ofMedicine 361-366 (10.1056/nejma0902903); BMS-833923 (also known asXL139) described in, e.g., in Siu L. et al., J. Clin. Oncol. 2010;28:15s (suppl; abstr 2501); and National Institute of Health ClinicalTrial Identifier No. NCT006701891; LDE-225 described, e.g., in Pan S. etal., ACS Med. Chem. Lett., 2010; 1(3): 130-134; LEQ-506 described, e.g.,in National Institute of Health Clinical Trial Identifier No.NCT01106508; PF-04449913 described, e.g., in National Institute ofHealth Clinical Trial Identifier No. NCT00953758; Hedgehog pathwayantagonists provided in U.S. Patent Application Publication No.2010/0286114; SMOi2-17 described, e.g., U.S. Patent ApplicationPublication No. 2010/0093625; SANT-1 and SANT-2 described, e.g., inRominger C. M. et al., J. Pharmacol. Exp. Ther. 2009; 329(3):995-1005;1-piperazinyl-4-arylphthalazines or analogues thereof, described inLucas B. S. et al., Bioorg. Med. Chem. Lett. 2010; 20(12):3618-22.

Other chemotherapeutic agents include, but are not limited to,anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRHagonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamideand bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA),phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A(2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide,trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas(e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g.busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide),platinum containing compounds (e.g. cisplatin, carboplatin,oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine,and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalentsuch as nanoparticle albumin-bound paclitaxel (Abraxane),docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin),polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex,CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxelbound to the erbB2-recognizing peptide EC-1), and glucose-conjugatedpaclitaxel, e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate;docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate,teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan,irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors(e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMPdehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin,and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea anddeferoxamine), uracil analogs (e.g. 5-fluorouracil (5-FU), floxuridine,doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosineanalogs (e.g. cytarabine (ara C), cytosine arabinoside, andfludarabine), purine analogs (e.g. mercaptopurine and Thioguanine),Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylationinhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g.1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g.staurosporine), actinomycin (e.g. actinomycin D, dactinomycin),bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline(e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin,idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDRinhibitors (e.g. verapamil), Ca2+ ATPase inhibitors (e.g. thapsigargin),imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g.,axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™,AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®),gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib(TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272),nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®,SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474),vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab(AVASTINO), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab(VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib(NEXAVAR®), everolimus (AFINITORO), alemtuzumab (CAMPATH®), gemtuzumabozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765,AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523,PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154,CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/orXL228), proteasome inhibitors (e.g., bortezomib (Velcade)), mTORinhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus(RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235(Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502(Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)),oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed,cyclophosphamide, dacarbazine, procarbizine, prednisolone,dexamethasone, campathecin, plicamycin, asparaginase, aminopterin,methopterin, porfiromycin, melphalan, leurosidine, leurosine,chlorambucil, trabectedin, procarbazine, discodermolide, carminomycingaminopterin, and hexamethyl melamine.

Exemplary biotherapeutic agents include, but are not limited to,interferons, cytokines (e.g., tumor necrosis factor, interferon α,interferon γ), vaccines, hematopoietic growth factors, monoclonalserotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1,2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) andantibodies (e.g. Herceptin (trastuzumab), T-DM1, AVASTIN (bevacizumab),ERBITUX (cetuximab), Vectibix (panitumumab), Rituxan (rituximab), Bexxar(tositumomab)).

In some embodiments, the chemotherapeutic is selected from HSP90inhibitors. The HSP90 inhibitor can be a geldanamycin derivative, e.g.,a benzoquinone or hygroquinone ansamycin HSP90 inhbitor (e.g., IPI-493and/or IPI-504). Non-limiting examples of HSP90 inhibitors includeIPI-493, IPI-504, 17-AAG (also known as tanespimycin or CNF-1010),BIIB-021 (CNF-2024), BUB-028, AUY-922 (also known as VER-49009),SNX-5422, STA-9090, AT-13387, XL-888, MPC-3100, CU-0305, 17-DMAG,CNF-1010, Macbecin (e.g., Macbecin I, Macbecin II), CCT-018159,CCT-129397, PU-H71, or PF-04928473 (SNX-2112).

In some embodiments, the chemotherapeutic is selected from PI3Kinhibitors (e.g., including those PI3K inhibitors provided herein andthose PI3K inhibitors not provided herein). In some embodiment, the PI3Kinhibitor is an inhibitor of delta and gamma isoforms of PI3K. In someembodiments, the PI3K inhibitor is an inhibitor of alpha isoforms ofPI3K. In other embodiments, the PI3K inhibitor is an inhibitor of one ormore alpha, beta, delta and gamma isoforms of PI3K. Exemplary PI3Kinhibitors that can be used in combination are described in, e.g., WO09/088990, WO 09/088086, WO 2011/008302, WO 2010/036380, WO 2010/006086,WO 09/114870, WO 05/113556; US 2009/0312310, and US 2011/0046165.Additional PI3K inhibitors that can be used in combination with thepharmaceutical compositions, include but are not limited to, AMG-319,GSK 2126458, GDC-0980, GDC-0941, Sanofi XL147, XL499, XL756, XL147,PF-46915032, BKM 120, CAL-101 (GS-1101), CAL 263, SF1126, PX-886, and adual PI3K inhibitor (e.g., Novartis BEZ235). In one embodiment, the PI3Kinhibitor is an isoquinolinone.

In some embodiments, provided herein is a method for using the acompound as provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, in combination withradiation therapy in inhibiting abnormal cell growth or treating thehyperproliferative disorder in the subject. Techniques for administeringradiation therapy are known in the art, and these techniques can be usedin the combination therapy described herein. The administration of thecompound as provided herein in this combination therapy can bedetermined as described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g., At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner as provided herein include both solids and liquids. Byway of non-limiting example, the radiation source can be a radionuclide,such as 1-125, I-131, Yb-169, Ir-192 as a solid source, I-125 as a solidsource, or other radionuclides that emit photons, beta particles, gammaradiation, or other therapeutic rays. The radioactive material can alsobe a fluid made from any solution of radionuclide(s), e.g., a solutionof I-125 or I-131, or a radioactive fluid can be produced using a slurryof a suitable fluid containing small particles of solid radionuclides,such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in agel or radioactive micro spheres.

Without being limited by any theory, the compounds as provided herein,or a pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,can render abnormal cells more sensitive to treatment with radiation forpurposes of killing and/or inhibiting the growth of such cells.Accordingly, provided herein is a method for sensitizing abnormal cellsin a subject to treatment with radiation which comprises administeringto the subject an amount of a compound as provided herein orpharmaceutically acceptable forms (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, which amount is effective is sensitizing abnormalcells to treatment with radiation. The amount of the compound used inthis method can be determined according to the means for ascertainingeffective amounts of such compounds described herein.

The compounds as provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be used incombination with an amount of one or more substances selected fromanti-angiogenesis agents, signal transduction inhibitors, andantiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound as provided herein and pharmaceutical compositions describedherein. Anti-angiogenesis agents include, for example, rapamycin,temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, andbevacizumab. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931, 788 (published Jul. 28, 1999), WO90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. In some embodiments, MMP-2 and MMP-9inhibitors are those that have little or no activity inhibiting MMP-1.Other embodiments include those that selectively inhibit MMP-2 and/orAMP-9 relative to the other matrix-metalloproteinases (i.e., MAP-1,MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, andMMP-13). Some non-limiting examples of MMP inhibitors are AG-3340, RO32-3555, and RS 13-0830.

Autophagy inhibitors include, but are not limited to, chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including, but not limited to ATG5 (which are implicated inautophagy), can also be used.

For treating renal carcinoma, one can combine a a compound as providedherein, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, or pharmaceuticalcompositions as provided herein, with sorafenib and/or avastin. Fortreating an endometrial disorder, one can combine a compound as providedherein with doxorubincin, taxotere (taxol), and/or cisplatin(carboplatin). For treating ovarian cancer, one can combine a compoundas provided herein with cisplatin (carboplatin), taxotere, doxorubincin,topotecan, and/or tamoxifen. For treating breast cancer, one can combinea compound as provided herein with taxotere (taxol), gemcitabine(capecitabine), tamoxifen, letrozole, tarceva, lapatinib, PD0325901,avastin, herceptin, OSI-906, and/or OSI-930. For treating lung cancer,one can combine a compound as provided herein with taxotere (taxol),gemcitabine, cisplatin, pemetrexed, Tarceva, PD0325901, and/or avastin.

In some embodiments, the disorder to be treated, prevented and/ormanaged is hematological cancer, e.g., lymphoma (e.g., T-cell lymphoma;NHL), myeloma (e.g., multiple myeloma), and leukemia (e.g., CLL), and acompound provided herein is used in combination with: HDAC inhibitorssuch as vorinostat and romidepsin; mTOR inhibitors such as everolmus;anti-folates such as pralatrexate; nitrogen mustard such asbendamustine; gemcitabine, optionally in further combination withoxaliplatin; rituximab.cyclophosphamide combination; PI3K inhibitorssuch as GS-1101, XL 499, GDC-0941, and AMG-319; or BTK inhibitors suchas ibrutinib and AVL-292.

7. Methods of Determining Biological Activity

Methods of determining the activity of compounds provided herein forvarious therapeutic uses are well known in the art. These include, butare not limited to, high throughput screening to find compounds thatbind to and/or modulate the activity of isolated MAGL, as well as animaland cellular models of therapies. Certain specific assay protocols areprovided herein below in the Examples section.

The assays for compounds described herein are amenable to highthroughput screening. Any methods known in the art can be used for assayof MAGL inhibition activity. One exemplary method is an assay usingfluorophosphonate agents, such as isopropyldodecylfluorophosphonate(IDFP), described in Nomura et al., Nat Chem Biol, 4: 373-378 (2008),which is incorporated herein by reference. Another exemplary method is aspectrophotometric method using thioester containing analogue of 2-AGdescribed in Ulloa et al., The AAPS Journal, 12(2): 197-201 (2010),which is incorporated herein by reference.

Methods for screening for an antinociceptive effect are well known toone of ordinary skill in the art. For instance, the test compounds canbe administered to the subject animals in the mouse hot-plate test andthe mouse formalin test and the nociceptive reactions to thermal orchemical tissue damage measured (for example, see U.S. Pat. No.6,326,156 which teaches methods of screening for antinociceptiveactivity; see also Cravatt et al. Proc. Natl. Acad. Sci. U.S.A. (2001)98:9371-9376).

Two pharmacologically validated animal models of anxiety are theelevated zero maze test, and the isolation-induced ultrasonic emissiontest. The zero maze consists of an elevated annular platform with twoopen and two closed quadrants and is based on the conflict between ananimal's instinct to explore its environment and its fear of openspaces, where it can be attacked by predators (see, for example,Bickerdike, M. J. et al., Eur. J. Pharmacol., (994) 271, 403-411;Shepherd, J. K. et al., Psychopharmacology, (1994) 116, 56-64).Clinically used anxiolytic drugs, such as the benzodiazepines, increasethe proportion of time spent in, and the number of entries made into,the open compartments.

A second test for an anti-anxiety compound is the ultrasonicvocalization emission model, which measures the number of stress-inducedvocalizations emitted by rat pups removed from their nest (see, forexample, Insel, T. R. et al., Pharmacol. Biochem. Behav., 24, 1263-1267(1986); Miczek, K. A. et al., Psychopharmacology, 121, 38-56 (1995);Winslow, J. T. et al., Biol. Psychiatry, 15, 745-757 (1991).

The effect of the compound in the treatment of depression can be testedin the model of chronic mild stress induced anhedonia in rats. Thismodel is based on the observation that chronic mild stress causes agradual decrease in sensitivity to rewards, for example consumption ofsucrose, and that this decrease is dose-dependently reversed by chronictreatment with antidepressants. The method has previously been describedand more information with respect to the test appears from Willner,Paul, Psychopharmacology, 1997, 134, 319-329.

Another test for antidepressant activity is the forced swimming test(Nature 266, 730-732, 1977). In this test, animals are administered anagent, such as by the intraperitoneal route or by the oral route, 30 or60 minutes before the test. The animals are placed in a crystallizingdish filled with water and the time during which they remain immobile isclocked. The immobility time is then compared with that of the controlgroup treated with distilled water. Imipramine 25 mg/kg. can be used asthe positive control. The antidepressant compounds decrease theimmobility time of the mice thus immersed.

Another test for antidepressant activity is the caudal suspension teston the mouse (Psychopharmacology, 85, 367-370, 1985). In this test,animals can be treated with the study compound by the intraperitonealroute or by the oral route 30 or 60 minutes before the test. The animalsare then suspended by the tail and their immobility time isautomatically recorded by a computer system. The immobility times arethen compared with those of a control group treated with distilledwater. Imipramine 25 mg/kg can be used as the positive control.Antidepressant compounds decrease the immobility time of the mice.

Animals models are available to one of ordinary skill in the art forstudying anticonvulsant activity of test compounds. See for instance,U.S. Pat. No. 6,309,406 and U.S. Pat. No. 6,326,156 which describemethods for performing such tests.

Methods for studying sleep inducing compounds are well known to one ofordinary skill in the art. For example, the compounds can beadministered to a test animal (e.g., rat or mouse) or a human and thesubsequent time (e.g., onset, duration) spent sleeping (e.g., eyesclosed, motor quiescence) can be monitored. See also WO 98/24396.

Methods for screening compounds which induce catalepsy are also wellknown to one of ordinary skill in the art. See Quistand et al. inToxicology and Applied Pharmacology 173: 48-55 (2001). See Cravatt etal. Proc. Natl. Acad. Sci. U.S.A. 98:9371-9376 (2001).

Methods of assessing appetitive behavior are known to one of ordinaryskill in the art. For instance, Maruani et al. (U.S. Pat. No. 6,344,474)teach two such assays. One method of assessing the effect on appetitebehavior is to administer a compound to a rat and assess its effect onthe intake of a sucrose solution. This method is taught in W. C. Lynchet al., Physiol. Behav., 1993, 54, 877-880.

Methods for assessing the effect of MAGL inhibitors on inflammatorybowel disease (IBD) are well known in the art. See Alhouayek et al.,FASEB J. 2011, 25:2711-2721. Diseased mice treated with MAGL inhibitorsdisplay increased 2-arachidonoylglycerol levels, leading to a reductionof colon alterations and colonic expression of proinflammatory cytokines

Methods for studying the effect of MAGL inhibitors in muriune models ofParkinson's disease, Alzheimer's disease and other neurodegenerativedisorders include assessing the subjects for decreases in prostaglandinand other eicosanoids in the brain upon MAGL inhibitor adminstration.See Nomura et al., Science 2011, 334:809-813.

EXAMPLES

The following examples are provided to better illustrate what isprovided herein, but are not intended to limit the disclosure in anyway.

1. General Synthetic Schemes 1.1 Method 1

General conditions for the preparation of 3-bromo-biphenyls:Bromoiodobenzene (1.00 equiv), boronic acid (1.01 equiv),bis(triphenylphosphine)palladium chloride (0.03 equiv) and sodiumbicarbonate (3.0 equiv) are combined in n-propanol/water (4:1 v:v, 0.25Mwith respect to iodide). The flask is fitted with a reflux condenser anddegassed with vacuum, backfilling with argon, for three cycles. Thereaction is heated at reflux overnight and then judged complete by thinlayer chromatography or LC/MS, at which point it is quenched with 1NNaOH (2 equiv), cooled, diluted with water, and extracted thrice withethyl acetate. The combined organic phases are washed with brine, driedover sodium sulfate, and concentrated in vacuo. If necessary, theconcentrated reaction mixture is purified by flash silica gelchromatography (ethyl acetate/hexanes) to provide the desired3-bromobiphenyl.

1.2 Method 2

General conditions for the preparation of 3-bromo-biphenyls:Bromoiodobenzene (1.00 equiv), boronic acid (1.01 equiv),bis(triphenylphosphine)palladium chloride (0.03 equiv) and sodiumbicarbonate (3.0 equiv) are combined in 1,4-dioxane/water (4:1 v:v, 0.2Mwith respect to iodide). The flask is fitted with a reflux condenser anddegassed with vacuum, backfilling with argon, for three cycles. Thereaction is heated at 75-100° C. overnight and then judged complete bythin layer chromatography or LC/MS, at which point it is quenched withsaturated aqueous sodium bicarbonate, cooled, diluted with water, andextracted thrice with ethyl acetate. The combined organic phases arewashed with brine, dried over sodium sulfate, and concentrated in vacuo.The concentrated reaction mixture is purified by flash silica gelchromatography (ethyl acetate/hexanes) to provide the desired3-bromobiphenyl.

1.3 Method 3

General conditions for the preparation of 3-bromo-biphenyls:Bromoiodobenzene (1.00 equiv), boronic acid (1.01 equiv),[1,1,-bis(triphenylphosphino)ferrocene]palladium[II] chloridedichloromethane adduct (0.02 equiv) and sodium bicarbonate (3.0 equiv)are combined in 1-propanol/water (4:1 v:v, 0.3M with respect to iodide).The flask is fitted with a reflux condenser and degassed with vacuum,backfilling with argon, for three cycles. The reaction is heated atreflux overnight and then judged complete by thin layer chromatographyor LC/MS, at which point it is cooled, diluted with water, and extractedthrice with ethyl acetate. The combined organic phases are washed withbrine, dried over sodium sulfate, and concentrated in vacuo. If needed,the concentrated reaction mixture is purified by flash silica gelchromatography (ethyl acetate/hexanes) to provide the desired3-bromobiphenyl.

1.4 Method 4

General conditions for the preparation of biphenyl-3-boronic acidpinacol esters: 3-Bromobiphenyl (1.0 equiv), bis(pinacolato)diboron (2.0equiv), [1,1,-bis(triphenylphosphino)ferrocene]palladium[II] chloridedichloromethane adduct (0.1 equiv), cesium carbonate (3.0 equiv), andpotassium acetate (1.0 equiv) are combined in a sealed flask and purgedof oxygen with a flow of dry argon. Dimethylsulfoxide (0.25M withrespect to bromide) is added and the resulting suspension is stirred ina 70° C. bath for 1 h, at which time LC/MS indicated reactioncompletion. The reaction mixture is cooled and diluted with water andmethyl tert-butyl ether, adding saturated sodium chloride solution toimprove separation. The resultant emulsion is filtered through celite;the filtrate is separated and the organic phase washed with brine anddried over sodium sulfate. Concentration in vacuo and flashchromatography on silica gel affords the desired biphenyl-3-boronic acidpinacol ester.

1.5 Method 5

General conditions for the preparation of biphenyl-3-boronic acids:Pinacol boronate (1.0 equiv) is dissolved in acetone (0.1 M) and thesolution is saturated with water until two layers form, then adding afew drops more acetone to restore homogeneity. Sodium periodate (4.0equiv) and ammonium acetate (4 equiv) are added and the suspensionstirred rapidly overnight. At reaction completion, as measured by LC/MS,the reaction mixture is diluted with water and extracted thrice intoethyl acetate, adding saturated aqueous sodium chloride as needed toachieve layer separation. The organic layer is reduced to 10-15% of itsoriginal volume in vacuo and extracted twice with 1N aqueous sodiumhydroxide. This aqueous layer is washed sparingly with ethyl acetate,discarding the organic phases, and then acidified with sulfuric acid toa pH below 5. Extraction thrice with ethyl acetate, followed by washingthe combined organic phases with brine and drying over sodium sulfate,provides, after concentration in vacuo, the desired biphenyl-3-boronicacid as a white powder.

2. Exemplary Synthesis 2.1 Example 1

4′-Carbamoylbiphenyl-3-boronic acid was prepared in 3 steps from3-iodobromobenzene using Method 1, Method 4, and Method 5. [M+H]+=242.15m/z.

2.2 Example 2

4′-(Acetamidomethyl)biphenyl-3-boronic acid was prepared in 3 steps from3-iodobromobenzene using Method 3, Method 4, and Method 5.[M−NHAc]+=211.16 m/z.

2.3 Example 3

4′-Carbamoyl-6-fluorobiphenyl-3-boronic acid was prepared in 3 stepsfrom 4-bromo-1-fluoro-2-iodobenzene using Method 1, Method 4, and Method5. [M+H]+=260.10 m/z.

2.4 Example 4

4′-Carbamoyl-4-fluorobiphenyl-3-boronic acid was prepared in 3 stepsfrom 2-bromo-1-fluoro-4-iodobenzene using Method 1, Method 4, and Method5. [M+H]+=260.10 m/z.

2.5 Example 5

4′-(Methylsulfonylamino)biphenyl-3-boronic acid was prepared in 3 stepsfrom 3-iodobromobenzene using Method 3, Method 4, and Method 5.[M+NH₄]+=310.02 m/z.

2.6 Example 6

4′-(Aminosulfonyl)biphenyl-3-boronic acid was prepared in 3 steps from3-iodobromobenzene using Method 3, Method 4, and Method 5.[M+NH₄]+=295.05 m/z.

2.7 Example 7

4′-Carbamoyl-5-fluorobiphenyl-3-boronic acid was prepared in 3 stepsfrom 3-bromo-1-fluoro-5-iodobenzene using Method 1, Method 4, and Method5. [M+H]+=260.10 m/z.

2.8 Example 8

4′-(Methylsulfonylaminomethyl)biphenyl-3-boronic acid was prepared in 3steps from 3-iodobromobenzene using Method 3, Method 4, and Method 5.[M−NHMs]+=211.16 m/z.

2.9 Example 9

4′-(Methylsulfonylamino)-6-fluorobiphenyl-3-boronic acid was prepared in3 steps from 4-bromo-1-fluoro-2-iodobenzene using Method 2, Method 4,and Method 5. [M+NH₄]+=327.06 m/z.

2.10 Example 10

4′-(Aminosulfonyl)-6-fluorobiphenyl-3-boronic acid was prepared in 3steps from 4-bromo-1-fluoro-2-iodobenzene using Method 3, Method 4, andMethod 5. [M+NH₄]+=313.04 m/z.

2.11 Example 11

4′-Ureidobiphenyl-3-boronic acid was prepared in 3 steps from3-iodobromobenzene (using 4-ureidophenylboronic acid pinacol esterinstead of a boronic acid in Method 2) using Method 2, Method 4, andMethod 5. [M+H]+=257.12 m/z.

2.12 Example 12

4′-Acetamido-6-fluorobiphenyl-3-boronic acid was prepared in 3 stepsfrom 4-bromo-1-fluoro-2-iodobenzene using Method 2, Method 4, and Method5. [M+H]+=274.09 m/z.

2.13 Example 13

4′-(Methylsulfonylamino)-5-trifluoromethylbiphenyl-3-boronic acid wasprepared in 3 steps from 3-bromo-5-iodobenzotrifluoride using Method 2,Method 4, and Method 5. [M+NH₄]+=377.08 m/z.

2.14 Example 14

4′-(Cyclopropylsulfonylamino)-6-fluorobiphenyl-3-boronic acid wasprepared in 3 steps from 4-bromo-1-fluoro-2-iodobenzene using Method 2,Method 4, and Method 5. [M+NH₄]+=353.10 m/z.

2.15 Example 15

4-(Phenylamino)phenylboronic acid was prepared in 2 steps from4-bromodiphenylamine using Method 4 and Method 5. [M+H]+=214.14 m/z.

2.16 Example 16

4-(Phenylamino)phenyl boronic acid pinacol ester was prepared in 1 stepfrom 4-bromodiphenylamine using Method 4. A portion of this product (1equiv) was dissolved in acetonitrile/tetrahydrofuran 1:1 (concentration0.2 M) and treated with pyridine (6 equiv) and phenyl chloroformate (1.8equiv). After heating at 50° C. for 18 h, the reaction was quenched byaddition of water, diluted with saturated aqueous sodium bicarbonate,and extracted into dichloromethane. The organic layer was washed withsaturated sodium chloride solution, dried on sodium sulfate, andconcentrated in vacuo. Silica gel flash chromatography of the residue(ethyl acetate/hexanes) afforded a mixture of the intermediate phenylcarbamate and unreacted amine. This crude mixture was treated accordingto Method 5 to afford the desired N-(phenoxycarbonyl)diphenylamine-4-boronic acid. [M+H]+=334.08 m/z.

2.17 Example 17

3-Fluoro-4-bromobenzoic acid (1 equiv) was suspended in polyphosphoricacid (concentration about 0.4 M) in an oil bath heated to 110° C.2-Aminothiophenol (1 equiv) was added and the mixture stirred in thebath during 2 hours, at which time LC/MS indicated reaction completion.The reaction mixture was poured onto a mixture of ice and saturatedammonium hydroxide solution, rinsing the flask with water, and stirredrapidly. The white precipitate was collected by filtration, washed withwater, and dried in vacuo to give pure2-(4-bromo-3-fluorophenyl)benzothiazole. This material was treatedaccording to Method 4 and Method 5 to produce the desired2-(4-borono-3-fluorophenyl)benzothiazole. [M+H]+=274.08 m/z.

3. Assays 3.1 Inhibition of MAGL

Assay buffer was prepared adding 1 mM fresh TCEP into 25 mM HEPES, pH7.6, 100 mM KCL and 5% glycerol. Into 11 ml of assay buffer, 112 μl of100 nM MAGL solution was added to prepare MAGL buffer.P-nitrophenolacetate (NPA) buffer was prepared by dissolving 0.05 g ofNPA in DMSO to obtain the NPA stock (1 M final concentration), adding 22μl of the NPA stock into 202 μl of DMSO and 11 ml of assay buffer. Testcompound (1 mM) was serially diluted 3 times in DMSO to provide variousdecreasing concentrations (e.g., ranged from 1 mM (no dilution) to0.00046 mM (7 dilutions)).

Two microliter (2 μl) of the test compound, at various finalconcentrations obtained from above, was added to 98 μl of MAGL buffer,and the mixture was incubated at 37° C. for 30 minutes to 2 hours. Uponincubation, 100 μl of NPA buffer was added to the mixture and mixed 3times to initiate the reaction. The initial rate of the reaction wasmonitored using SpectraMax (410 nm, measured as mAU/min in the first 10minutes), and IC₅₀ values were determined.

All of the compounds described in Examples 1-17 were tested. It wasdetermined that the IC₅₀ values for these compounds range from about0.05 to about 2.2 μM, indicating that the compounds provided herein areeffective in inhibiting MAGL.

4. Animal Studies

Drug doses are given by oral gavage or intraperitoneal injection; only 1dose/drug/mouse. Test compound is supplied as a solid and is formulatedprior to use. Other test articles that can be used as controls includeJZL-184 and CB1 and CB2 receptor antagonists. Adult mice are used inthese studies, according to protocols and standards consistent withproper guidelines.

4.1 Determination of the Effective Doses in the Cannabinoid TetradBehavioral Test

Responses in tests of locomotion (open field), analgesia (tail flick),catalepsy (bar test), and/or hypothermia (rectal thermometer) areassessed in mice or rat after single I.P. or P.O. administration of thetest compound. Doses of the compound can be varied to determine the doseresponse relationships to minimum effective dose, maximum response, andduration of responses. Doses do not exceed maximum tolerated doses.JZL-184 can be used as a positive control. Reference protocols for thesestudies and comparison JZL-184 data are published, for example, in Long,et al., Nat. Chem. Biol. 5:37-44 (2008). At selected timepoints in thestudy, blood, plasma, or other tissue samples are collected for lateranalysis of the test compound, 2-arachidonylglycerol ester, or otherendocannabinoids.

Antinociceptive Effects—Tail Flick Test

On the testing day, each animal was placed into a holding tube andallowed to acclimate for 2-5 minutes prior to any testing. The heat lampof the tail flick apparatus was set to an intensity sufficient toproduce a control latency of 2-4 seconds (as determined by baselinevalues) and a 10 seconds maximum was set up to prevent tissue damage.Each animal was subjected to the heating beam 3 times, at the sameintensity, with a delay of 10 seconds in between each test. The middleportion of the animal's tail was the heating zone each time, but eachsubsequent test was a different part of that section. Each latency timewas recorded. Baseline control latencies were determined for each animalone day prior to drug administration.

After control values were measured, the animals were placed intoseparate groups, weighed, and then dosed. The animals were split into 3equal cohorts and dosed/tested at 3 consecutive times during the day. Asingle i.p. administration of an appropriate dose (e.g., 100 mg/kg) wasgiven to each of the animals. The dosing times were recorded for eachgroup. The animals were then tested every 30 minutes after being dosedup to 2 hours, and tail flick latency values were recorded. The degreeof antinociception was expressed as % MPE (maximum possible effect),which was calculated as:

% MPE=[(test latency−control latency)/(10 sec−test latency)]×100

Any animal that reach the 10 seconds heating limit was considered tohave achieved a complete analgesia.

Hypothermia Effects

On the same day as tail flick testing, each animal's core temperaturewas monitored using a Thermalert Monitoring Thermometer and aspecialized animal probe inserted approximately 25 mm. An initialtemperature for each animal was measured and recorded directly beforedrug administration. Post drug administration, each animal was measuredevery 30 minutes for 2 hours. Core temperatures were measured andrecorded alongside tail flick testing at each time point. The data forhypothermia were expressed as the difference between pre and post dosetemperatures at each time point.

Δ° C.=(Baseline Temperature−Post Dose Temperature).

Certain compounds provided herein were tested in tail flick assay andhypothermia assay. It was determined that certain compounds providedherein showed antinociceptive and hypothermic effects similar to JZL-184in mice, as well as antinociceptive and hypothermic effects in rats.

4.2 Assessment of Anti-Allodynic Effects in Mouse CCI Model ofNeuropathic Pain

According to protocols published in Kinsey et al., J. Pain, 11:1420-1428(2010), compound was tested for single-dose activity in the mousechronic constriction injury (CCI) model. Hypersensitivity to mechanical(von Frey) or cold (acetone) stimuli was assessed. Doses were selectedbased on active doses from the cannabinoid tetrad tests described inSection 4.1, above. JZL-184 was used as a positive control, and CBreceptor agonists can be co-administered to assess the mechanism ofeffects exerted by the compound. At selected timepoints in the study,blood, plasma, or other tissue samples were collected for later analysisof the compound, 2-arachidonylglycerol ester (2-AG), or otherendocannabinoids.

The anti-allodynic effects of certain compounds provided herein weretested. It was determined that certain compounds provided herein blockedCCI-induced allodynia. In one embodiment of the experiment, the dose ofthe tested compounds was about 100 mg/kg.

4.3 Assessment of Activity in Reducing NASID-Induced Gastric Hemorrhagesin Mice

Non-steroidal anti-inflammatory drugs are widely used analgesics,however, their chronice use results in potentially life threateninggastro-intestinal side effects. According to protocols published inKinsey, et al., FASEB J., 25:807 (2011), compound was tested for itsrability to protect against NSAID-induced gastric hemorrhages in mice.Doses were selected based on active doses from the cannabinoid tetradtests described in Section 4.1, above. JZL-184 was used as a positivecontrol, and CB receptor agonists can be co-administered to assess themechanism of effects exerted by the compound. At selected timepoints inthe study, blood, plasma, or other tissue samples were collected forlater analysis of the compound, 2-AG, or inflammatory cytokines

The gastric anti-inflammatory effects of certain compounds providedherein were tested. It was determined that certain compounds providedherein blocked diclofenac-induced gastric lesions in mice. In oneembodiment of the experiment, the dose of the tested compounds is fromabout 100 mg/kg to about 200 mg/kg.

4.4 Assessment of T-Cell Mediated Reaction Determined by Delayed TypeHypersensitivity (DTH) Assay

Assessment of compound activity was determined by using a t-cellmediated response model. The model was established by sensitizing miceon two consecutive days (0,1) with a solution of2,4-dinitrofluorobenzene (DNFB) dissolved in a 4:1 acetone/olive oilvehicle and applied topically (20 uL/foot 0.05%) to both hind limbfootpads. On day 5, test compounds, positive control (Dexemethasone) orvehicle was administered 30 minutes prior to challenging the mice. Micewere anesthetized and challenged with DNFB (0.25%) applied to one ear bytopical application to both inner and outer ear. On the correspondingear (of the same mouse) vehicle was topically applied in the same manor.On day 6, following a 24 hour period, mice were re-anesthetized. Thethickness of both ears was measured using digital micrometers. Thedifference between the DNFB treated ear and vehicle ear was recorded.Blood and ears were collected for cytokine evaluation using the MesoScale Discovery system. Serum was separated off from the blood. The MSDmouse pro-inflammatory cytokine 7 plex platform was used for analysiswith the following cytokines evaluated; IL-1β, IL-12p70, IFNγ, IL-6,KC/GRO, IL-10, and TNF-α. Ears from DNFB and vehicle treatment wereimmediately placed in a vial and frozen in liquid nitrogen. These werepulverized into a powder. A lysate containing ear powder and buffer wasrun on the MSD mouse pro-inflammatory cytokine 7 plex platform foranalysis.

Certain compounds provided herein were tested in the DTH mouse model. Itwas determined that certain compounds provided herein decreased earswelling dose dependently in the DTH mouse model. It was also determinedthat certain compounds provided herein decreased localized IFNγ, IL-6,IL-10, and KC/GRO levels, and increased localized IL-1β levels in DNFBtreated ears compared to vehicle. In one embodiment of the experiment,the dose of the tested compounds is from about 50 mg/kg to about 200mg/kg.

4.5 Assessment of Inhibition of Mast Cell Activation Using an AcuteInflammatory Assay (AIM)

Assessment of compound activity was determined using an acute phasemodel. Mice were dosed with compound, positive control (naproxen) orvehicle. One hour later mice were anesthetized and challenged on one eartopically on both the inner and outer sides with DNFB (0.55%). Thecorresponding ear had vehicle applied in the same manor. Four hours postapplication of the DNFB mice were re-anesthetized. The thickness of bothears was measured using digital micrometers. The difference between theDNFB treated ear and vehicle ear was recorded. Blood and ears werecollected for cytokine evaluation using the Meso Scale Discovery system.Serum was separated off from the blood. The MSD mouse pro-inflammatorycytokine 7 plex platform was used for analysis with the followingcytokines evaluated; IL-1β, IL-12p70, IFNγ, IL-6, KC/GRO, IL-10, andTNF-α. Ears from DNFB and vehicle treatment were immediately placed in avial and frozen in liquid nitrogen. These were pulverized into a powder.A lysate containing ear powder and buffer was run on the MSD mousepro-inflammatory cytokine 7 plex platform for analysis.

Certain compounds provided herein were tested in the AIM model. It wasdetermined that certain compounds provided herein decreased ear swellingdose dependently in the AIm model. It was also determined that certaincompounds provided herein increased serum IL-6, IL-10, and KC/GRO levelscompared to vehicle, increased localized IL-6 levels in DNFB treatedears compared to vehicle, and decreased localized KC/GRO levels in DNFBtreated ears compared to vehicle. In one embodiment of the experiment,the dose of the tested compounds is from about 100 mg/kg to about 300mg/kg.

4.6 Tumor Cell Line Proliferation Assay

The ability of one or more subject compounds to inhibit tumor cell lineproliferation can be determined according to standard procedures knownin the art. For instance, an in vitro cellular proliferation assay canbe performed to measure the metabolic activity of live cells. The assayis performed in a 96 well microtiter plate using Alamar Blue reduction.Human tumor cell lines are obtained from ATCC (e.g., MCF7, U-87 MG,MDA-MB-468, PC-3), grown to confluency in T75 flasks, trypsinized with0.25% trypsin, washed one time with Tumor Cell Media (DMEM+10% FBS), andplated in 90 μl at 5,000 cells/well in Tumor Cell Media. A compoundprovided herein is diluted in Tumor Cell Media and added in a 10 μlvolume. Plates are incubated for 72 hours at 37° C. and 5% CO₂. A volumeof 10 μl of Alamar Blue reagent is added to each well and plates areincubated for 3 hours at 37° C. and 5% CO₂. Alamar Blue fluoresce isread at 560Ex/590Em, and IC₅₀ values are calculated using GraphPad Prism5.

4.7 Antitumor Activity In Vivo

The compounds provided herein can be evaluated in a panel of human andmurine tumor models.

Clinically-Derived Ovarian Carcinoma Model

This tumor model is established from a tumor biopsy of an ovarian cancerpatient. Tumor biopsy is taken from the patient. The compounds describedherein are administered to nude mice bearing staged tumors using anevery 2 days×5 schedule.

A2780Tax Human Ovarian Carcinoma Xenograft (Mutated Tubulin)

A2780Tax is a paclitaxel-resistant human ovarian carcinoma model. It isderived from the sensitive parent A2780 line by co-incubation of cellswith paclitaxel and verapamil, an MDR-reversal agent. Its resistancemechanism has been shown to be non-MDR related and is attributed to amutation in the gene encoding the beta-tubulin protein. The compoundsdescribed herein can be administered to mice bearing staged tumors on anevery 2 days×5 schedule.

HCT116/VM46 Human Colon Carcinoma Xenograft (Multi-Drug Resistant)

HCT116/VM46 is an MDR-resistant colon carcinoma developed from thesensitive HCT116 parent line. In vivo, grown in nude mice, HCT116/VM46has consistently demonstrated high resistance to paclitaxel. Thecompounds described herein can be administered to mice bearing stagedtumors on an every 2 days×5 schedule.

M5076 Murine Sarcoma Model

M5076 is a mouse fibrosarcoma that is inherently refractory topaclitaxel in vivo. The compounds described herein can be administeredto mice bearing staged tumors on an every 2 days×5 schedule.

One or more compounds as provided herein can be used in combinationother therapeutic agents in vivo in the multidrug resistant human coloncarcinoma xenografts HCT/VM46 or any other model known in the artincluding those described herein.

4.8 Determination of Time Course of Biochemical Changes inEndocannabinoids

Any blood, plasma, or tissue samples taken during the experimentsdescribed in Sections 4.1-4.7, above, can be analyzed for the testcompound, 2-AG, anandamide, other endocannabinoids, or inflammatorycytokines

What is claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable form thereof; wherein: A is a 6 to 10membered aryl, heteroaryl or heterocycle; X is a covalent bond or —NR⁵;R¹ and R² are each independently hydrogen, halogen, or an optionallysubstituted (C₁-C₆)alkyl; R³ is —C(O)NH₂, —(CH₂)_(n)—NHR⁶ or —SO₂R⁷, andR⁴ is hydrogen; or R³ and R⁴ taken together can form a 5 to 7 memberedring containing one or more heteroatoms selected from N, S and O,wherein one or more carbon or sulfur atoms on the ring can optionally besubstituted with one or more oxo group; R⁵ is hydrogen or —C(O)O—Y,wherein Y is an optionally substituted 6 to 10 membered aryl or anoptionally substituted (C₁-C₆)alkyl; R⁶ is an optionally substituted(C₁-C₆)alkyl, —SO₂R⁸ or —C(O)R⁹; R⁷, R⁸ and R⁹ are each independently anoptionally substituted (C₁-C₆)alkyl or an optionally substituted amino;and n is 0, 1, 2 or 3; wherein if R³ is —C(O)NH₂, then both R¹ and R²are not each hydrogen.
 2. The compound of claim 1, which is a compoundof formula (II):

or a pharmaceutically acceptable form thereof, wherein: R¹⁰ and R¹¹ areeach independently hydrogen, halogen or an optionally substituted(C₁-C₆)alkyl; R¹² is —C(O)NH₂, —(CH₂)_(n)—NHR¹⁴ or —SO₂R¹⁵ and R¹³ ishydrogen; or R¹² and R¹³ taken together can form a 5 to 7 membered ringcontaining one or more heteroatoms selected from N, S and O, wherein oneor more carbon or sulfur atoms on the ring can optionally be substitutedwith one or more oxo group; R¹⁴ is an optionally substituted(C₁-C₆)alkyl, —SO₂R¹⁶ or —C(O)R¹⁷; R¹⁵, R¹⁶ and R¹⁷ are eachindependently an optionally substituted (C₁-C₆)alkyl or an optionallysubstituted amino; and n is 0, 1, 2 or 3; wherein if R¹² is —C(O)NH₂,then both R¹⁰ and R¹¹ are not each hydrogen.
 3. The compound of claim 2,wherein R¹¹ is hydrogen.
 4. The compound of claim 3, wherein R¹⁰ ishydrogen or F.
 5. The compound of claim 2, wherein R¹⁰ is halogen or anoptionally substituted (C₁-C₆)alkyl, and R¹⁰ is para to the —B(OH)₂group.
 6. The compound of claim 2, wherein R¹³ is hydrogen.
 7. Thecompound of claim 6, wherein R¹² is —C(O)NH₂ or —(CH₂)_(n)—NHR¹⁴.
 8. Thecompound of claim 7, wherein R¹⁴ is an optionally substituted(C₁-C₆)alkyl, —SO₂R¹⁶, or —C(O)R¹⁷.
 9. The compound of claim 2, whereinR¹² is para to the covalent bond connecting the two phenyl rings. 10.The compound of claim 2, wherein R¹² and R¹³ together form a 5 memberedring, optionally having one or more heteroatoms selected from N, S andO.
 11. The compound of claim 2, which is a compound of formula (II′):

or a pharmaceutically acceptable form thereof, wherein: R¹⁰ is halogenor an optionally substituted (C₁-C₆)alkyl; R¹¹ is hydrogen, halogen oran optionally substituted (C₁-C₆)alkyl; R¹² is —C(O)NH₂,—(CH₂)_(n)—NHR¹⁴ or —SO₂R¹⁵ and R¹³ is hydrogen; or R¹² and R¹³ takentogether can form a 5 to 7 membered ring containing one or moreheteroatoms selected from N, S and O, wherein one or more carbon orsulfur atoms on the ring can optionally be substituted with one or moreoxo group; R¹⁴ is an optionally substituted (C₁-C₆)alkyl, —SO₂R¹⁶ or—C(O)R¹⁷; R¹⁵, R¹⁶ and R¹⁷ are each independently an optionallysubstituted (C₁-C₆)alkyl or an optionally substituted amino; and n is 0,1, 2 or
 3. 12. The compound of claim 2, wherein the compound is selectedfrom:

or a pharmaceutically acceptable form thereof.
 13. The compound of claim2, wherein the compound is selected from:

or a pharmaceutically acceptable form thereof.
 14. A compound of formula(III):

or a pharmaceutically acceptable form thereof, wherein: R¹⁸ is hydrogen,halogen, or an optionally substituted (C₁-C₆)alkyl; R¹⁹ is hydrogen or—C(O)O—Y, wherein Y is an optionally substituted 6 to 10 membered arylor an optionally substituted (C₁-C₆)alkyl; R²⁰ is hydrogen, —C(O)NH₂,—(CH₂)_(n)—NHR²¹ or —SO₂R²²; R²¹ is an optionally substituted(C₁-C₆)alkyl, —SO₂R²³ or —C(O)R²⁴; R²², R²³ and R²⁴ are eachindependently an optionally substituted (C₁-C₆)alkyl or an optionallysubstituted amino; and n is 0, 1, 2 or
 3. 15. The compound of claim 14,wherein R¹⁸ is hydrogen or halogen.
 16. The compound of claim 14,wherein R¹⁸ is methyl.
 17. The compound of claim 14, wherein R¹⁹ ishydrogen.
 18. The compound of claim 14, wherein R¹⁹ is —C(O)O—Y and Y isphenyl.
 19. The compound of claim 14, wherein R²¹ is an optionallysubstituted (C₁-C₆)alkyl.
 20. The compound of claim 14, wherein R²² isan optionally substituted (C₁-C₆)alkyl.
 21. The compound of claim 14,wherein R¹⁸ and R¹⁹ are both hydrogen.
 22. The compound of claim 14,wherein the compound is selected from:

or a pharmaceutically acceptable form thereof.
 23. A compound of formula(IV):

or a pharmaceutically acceptable form thereof, wherein: R²⁵ is hydrogen,halogen, or an optionally substituted (C₁-C₆)alkyl; R²⁶ is hydrogen,—C(O)NH₂, —(CH₂)_(n)—NHR²⁷ or —SO₂R²⁸; R²⁷ is an optionally substituted(C₁-C₆)alkyl, —SO₂R²⁹ or —C(O)R³⁰; R²⁸, R²⁹ and R³⁰ are eachindependently an optionally substituted (C₁-C₆)alkyl or an optionallysubstituted amino; and n is 0, 1, 2 or
 3. 24. The compound of claim 23,wherein the compound is:

or a pharmaceutically acceptable form thereof.
 25. A pharmaceuticalcomposition comprising a compound of claim 1 and one or morepharmaceutically acceptable carriers or excipients.
 26. A method fortreating a disorder or condition mediated by monoacylglycerol lipase(MAGL) comprising administering to a patient a therapeutically effectiveamount of a compound of claim
 1. 27. The method of claim 26, wherein thedisorder or condition is a CNS disorder.
 28. The method of claim 27,wherein the CNS disorder is neurotoxicity, neurotrauma, stroke, multiplesclerosis, spinal cord injury, epilepsy, a learning disorder orschizophrenia.
 29. The method of claim 28, wherein the stroke isischemic stroke.
 30. The method of claim 28, wherein the learningdisorder is attention deficit disorder.